Quinazolinone Modulators Of Nuclear Receptors

ABSTRACT

Compounds, pharmaceutical compositions and methods for modulating the activity of nuclear receptors are provided. In particular, quinazolinones are provided for modulating the activity of farnesoid X receptor (FXR) and/or orphan nuclear receptors.

FIELD OF THE INVENTION

Quinazolinones, compositions containing quinazolinones and methods formodulating the activity of nuclear receptors using quinazolinones areprovided. In particular, quinazolinones are provided for modulating theactivity of FXR and orphan nuclear receptors.

BACKGROUND OF THE INVENTION

Nuclear Receptors

Nuclear receptors are a superfamily of regulatory proteins that arestructurally and functionally related and are receptors for, e.g.,steroids, retinoids, vitamin D and thyroid hormones (see, e.g., Evans(1988) Science 240:889-895). These proteins bind to cis-acting elementsin the promoters of their target genes and modulate gene expression inresponse to ligands for the receptors.

Nuclear receptors can be classified based on their DNA bindingproperties (see, e.g., Evans, supra and Glass (1994) Endocr. Rev.15:391-407). For example, one class of nuclear receptors includes theglucocorticoid, estrogen, androgen, progestin and mineralocorficoidreceptors which bind as homodimers to hormone response elements (HREs)organized as inverted repeats (see, e.g., Glass, supra). A second classof receptors, including those activated by retinoic acid, thyroidhormone, vitamin D₃, fatty acids/peroxisome proliferators (i.e.,peroxisome proliferator activated receptor (PPAR)) and ecdysone, bind toHREs as heterodimers with a common partner, the retinoid X receptors(i.e., RXRs, also known as the 9-cis retinoic acid receptors; see, e.g.,Levin et al. (1992) Nature 355:359-361 and Heyman et al., (1992) Cell68:397-406).

RXRs are unique among the nuclear receptors in that they bind DNA as ahomodimer and are required as a heterodimeric partner for a number ofadditional nuclear receptors to bind DNA (see, e.g., Mangelsdorf et al.(1995) Cell 83:841-850). The latter receptors, termed the class IInuclear receptor subfamily, include many which are established orimplicated as important regulators of gene expression. There are threeRXR genes (see, e.g., Mangelsdorf et al. (1992) Genes Dev. 6:329-344),coding for RXRα, -β, and -γ, all of which are able to heterodimerizewith any of the class II receptors, although there appear to bepreferences for distinct RXR subtypes by partner receptors in vivo (see,e.g., Chiba et al. (1997) Mol. Cell. Biol. 17:3013-3020). In the adultliver, RXRα is the most abundant of the three RXRs (see, e.g.,Mangelsdorf et al. (1992) Genes Dev. 6:329-344), suggesting that itmight have a prominent role in hepatic functions that involve regulationby class II nuclear receptors. See also, Wan et al. (2000) Mol. Cell.Biol. 20:4436-4444.

Orphan Nuclear Receptors

Included in the nuclear receptor superfamily of regulatory proteins arenuclear receptors for whom the ligand is known and those which lackknown ligands. Nuclear receptors falling in the latter category arereferred to as orphan nuclear receptors. The search for activators fororphan receptors has led to the discovery of previously unknownsignaling pathways (see, e.g., Levin et al., (1992), supra and Heyman etal., (1992), supra). For example, it has been reported that bile acids,which are involved in physiological processes such as cholesterolcatabolism, are ligands for FXR (infra).

Since it is known that products of intermediary metabolism act astranscriptional regulators in bacteria and yeast, such molecules mayserve similar functions in higher organisms (see, e.g., Tomkins (1975)Science 189:760-763 and O'Malley (1989) Endocrinology 125:1119-1120).For example, one biosynthetic pathway in higher eukaryotes is themevalonate pathway, which leads to the synthesis of cholesterol, bileacids, porphyrin, dolichol, ubiquinone, carotenoids, retinoids, vitaminD, steroid hormones and farnesylated proteins.

FXR

FXR (originally isolated as RIP14 (retinoid X receptor-interactingprotein-14), see, e.g., Seol et al. (1995) Mol. Endocrinol. 9:72-85) isa member of the nuclear hormone receptor superfamily and is primarilyexpressed in the liver, kidney and intestine (see, e.g., Seol et al.,supra and Forman et al. (1995) Cell 81:687-693). It functions as aheterodimer with the retinoid X receptor (RXR) and binds to responseelements in the promoters of target genes to regulate genetranscription. The FXR-RXR heterodimer binds with highest affinity to aninverted repeat-1 (IR-1) response element, in which consensusreceptor-binding hexamers are separated by one nucleotide. FXR is partof an interrelated process, in that FXR is activated by bile acids (theend product of cholesterol metabolism) (see, e.g., Makishima et al.(1999) Science 284:1362-1365, Parks et al. (1999) Science 284:1365-1368,Wang et al. (1999) Mol. Cell. 3:543-553), which serve to inhibitcholesterol catabolism. See also, Urizar et al. (2000) J. Biol. Chem.275:39313-39317.

Nuclear Receptors and Disease

Nuclear receptor activity, including FXR and/or orphan nuclear receptoractivity has been implicated in a variety of diseases and disorders,including, but not limited to, hypercholesterolemia, and complicationsthereof, including without limitation coronary artery disease, anginapectoris, carotid artery disease, strokes, cerebral arteriosclerosis andxanthoma, (see, e.g., International Patent Application Publication No.WO 00/57915), osteoporosis and vitamin deficiency (see, e.g., U.S. Pat.No. 6,316,5103), hyperlipoproteinemia (see, e.g., International PatentApplication Publication No. WO 01/60818), hypertriglyceridemia,lipodystrophy, peripheral occlusive disease, ischemic stroke,hyperglycemia and diabetes mellitus (see, e.g., International PatentApplication Publication No. WO 01/82917), disorders related to insulinresistance including the cluster of disease states, conditions ordisorders that make up “Syndrome X” such as glucose intolerance, anincrease in plasma triglyceride and a decrease in high-densitylipoprotein cholesterol concentrations, hypertension, hyperuricemia,smaller denser low-density lipoprotein particles, and higher circulatinglevels of plasminogen activator inhibitor-1, atherosclerosis andgallstones (see, e.g., International Patent Application Publication No.WO 00/37077), disorders of the skin and mucous membranes (see, e.g.,U.S. Pat. Nos. 6,184,215 and 6,187,814, and International PatentApplication Publication No. WO 98/32444), obesity, acne (see, e.g.,International Patent Application Publication No. WO 00/49992), andcancer, Parkinson's disease and Alzheimer's disease (see, e.g.,International Patent Application Publication No. WO 00/17334). Theactivity of nuclear receptors, including FXR and/or orphan nuclearreceptors, has been implicated in physiological processes including, butnot limited to, bile acid biosynthesis, cholesterol metabolism orcatabolism, and modulation of cholesterol 7α-hydroxylase gene (CYP7A1)transcription (see, e.g., Chiang et al. (2000) J. Biol. Chem.275:10918-10924), HDL metabolism (see, e.g., Urizar et al. (2000) J.Biol. Chem. 275:39313-39317), hyperlipidemia, cholestasis, and increasedcholesterol efflux and increased expression of ATP binding cassettetransporter protein (ABC1) (see, e.g., International Patent ApplicationPublication No. WO 00/78972).

Thus, there is a need for compounds, compositions and methods ofmodulating the activity of nuclear receptors, including FXR and/ororphan nuclear receptors. Such compounds are useful in the treatment,prevention, or amelioration of one or more symptoms of diseases ordisorders in which nuclear receptor activity is implicated.

SUMMARY OF THE INVENTION

Compounds for use in compositions and methods for modulating theactivity of nuclear receptors are provided. In particular, compounds foruse in compositions and methods for modulating famesoid X receptor (FXR)and/or orphan nuclear receptors, are provided. In certain embodiments,the compounds are quinazolinones. In one embodiment, the compoundsprovided herein are agonists of FXR. In another embodiment, thecompounds provided herein are antagonists of FXR. Agonists that exhibitlow efficacy are, in certain embodiments, antagonists Antagonistsinclude both competitive and non-competitive antagonists. In anotherembodiment the compound is an inverse agonist, partial agonist orpartial antagonist

In one embodiment, the compounds for use in the compositions and methodsprovided herein have formula (I):

wherein:

m is an integer from 0 to 4;

R¹ is hydrogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, optionally substituted aralkyl,optionally substituted heteroaralkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocyclylalkyl, —OR⁷ or—N(R⁸)R⁹, with the proviso that R¹ is not 3- or4-(1,1,1,3,3,3-hexafluoro-2-hydroxy-2-propyl)phenyl;

R², R⁴, R⁵ and R⁶ are selected from (a) and (b) as follows:

-   -   (a) R² and R³ are selected from (i) and (ii) as follows: (i) R²        and R⁶ are each independently hydrogen, optionally substituted        alkyl, optionally substituted alkenyl, optionally substituted        alkynyl, optionally substituted aryl, optionally substituted        heteroaryl, optionally substituted cycloalkyl, optionally        substituted heterocyclyl, optionally substituted aralkyl,        optionally substituted heteroaralkyl, optionally substituted        cycloalkylalkyl, or optionally substituted heterocyclylalkyl;        or (ii) R² and R⁶ together form optionally substituted alkylene        or optionally substituted alkenylene; and    -   R⁴ and R⁵ are selected from (i) and (ii) as follows: (i) R⁴ and        R⁵ are each independently selected from hydrogen, optionally        substituted alkyl, optionally substituted alkenyl, optionally        substituted alkynyl, optionally substituted aryl, optionally        substituted heteroaryl, optionally substituted cycloalkyl,        optionally substituted heterocyclyl, optionally substituted        aralkyl, optionally substituted heteroaralkyl, optionally        substituted cycloalkylalkyl, optionally substituted        heterocyclylalkyl, —N(R⁸)R⁹, —OR⁷, —S(O)_(j)R¹¹ where j is 1 or        2, —B(R²²)₂, —P(R²²)₂, —P(O)(R²²)₂ and —C(E)R²³, where E is        selected from O, S and NR⁷; or (ii) R⁴ and R⁵ together form        optionally substituted alkylene, optionally substituted        alkenylene, optionally substituted alkyleneoxyalkylene or        optionally substituted alkyleneazaalkylene; or    -   (b) R² and R⁵, or R² and R⁴, or R⁶ and R⁵, or R⁶ and R⁴,        together form a 4, 5, 6 or 7 membered optionally substituted        heterocyclyl group, or a 5 or 6 membered optionally substituted        heteroaryl group; and the remainder of R², R⁴, R⁵ and R⁶ are        each independently selected as in (i) above;

each R³ is independently selected from the group consisting of halo,pseudohalo, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, optionally substituted aralkyl,optionally substituted heteroaralkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocyclylalkyl, —N(R¹²)R¹³,—OR¹⁴, —C(E)R¹⁵ where E is O, S or NR⁷, and —S(O)_(y)R¹⁶ where y is 0, 1or 2;

or any two R³ groups, which substitute adjacent carbons on the ring,together form optionally substituted alkylene, optionally substitutedalkenylene, optionally substituted alkylenedioxy, optionally substitutedthioalkylenoxy, or optionally substituted alkylenedithioxy;

each R⁷ is independently selected from the group consisting of hydrogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkylalkyl, and optionallysubstituted heterocyclylalkyl;

R⁸ and R⁹ are each independently selected from hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkylalkyl, optionallysubstituted heterocyclylalkyl, —S(O)_(j)R¹⁰ where j is 1 or 2, and—C(M)R¹¹, where M is selected from O and S;

or R⁸ and R⁹ together form alkylene, alkenylene, alkyleneoxyalkylene oralkyleneazaalkylene;

each R¹⁰ is independently selected from the group consisting ofoptionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkylalkyl, and optionallysubstituted heterocyclylalkyl;

each R¹¹ is independently selected from the group consisting ofoptionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkylalkyl, optionallysubstituted heterocyclylalkyl, —OR¹⁰ and —N(R⁷)₂;

R¹² and R¹³ are each independently selected from hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkylalkyl, optionallysubstituted heterocyclylalkyl, —C(M)R¹⁷ where M is O or S, and—S(O)_(j)R¹⁸ where j is 1 or 2;

or R¹² and R¹³ together form optionally substituted alkylene, optionallysubstituted alkenylene, optionally substituted alkyleneoxyalkylene oroptionally substituted alkyleneazaalkylene;

R¹⁴ is hydrogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, optionally substituted aralkyl,optionally substituted heteroaralkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocyclylalkyl or —C(M)R¹⁷where M is O or S;

R¹⁵ is hydrogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, optionally substituted aralkyl,optionally substituted heteroaralkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocyclylalkyl, —OH, —OR¹⁴ or—N(R¹²)R¹³;

R¹⁶ is hydrogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, optionally substituted aralkyl,optionally substituted heteroaralkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocyclylalkyl, —OH, —OR¹⁹ or—N(R²⁰)R²¹;

R¹⁷ is hydrogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, optionally substituted aralkyl,optionally substituted heteroaralkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocyclylalkyl, —OR¹⁹ or—N(R²)R²¹;

R¹⁸ is optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted cycloalkyl, optionallysubstituted heterocycyl, optionally substituted aralkyl, optionallysubstituted heteroaralkyl, optionally substituted cycloalkylalkyl,optionally substituted heterocyclylalkyl, —OR¹⁹ or —N(R²⁰)R²¹;

R¹⁹ is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl orheteroaralkyl;

R²⁰ and R²¹ are each independently selected from hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl,heterocyclylalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl,

or R²⁰ and R²¹ together form alkylene, alkenylene, alkyleneoxyalkyleneor alkyleneazaalkylene;

each R²² is independently selected from the group consisting ofoptionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkylalkyl, optionallysubstituted heterocyclylalkyl, —OR⁷ and —N(R⁷)₂;

R²³ is hydrogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, optionally substituted aralkyl,optionally substituted heteroaralkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocyclylalkyl, —OR¹⁰,—N(R⁷)₂, or —N(R⁷)N(R⁷)₂;

wherein each of the above R¹-R²³ groups, when substituted, aresubstituted with one or more substituents each independently selectedfrom Q¹, where Q¹ is halo, pseudohalo, hydroxy, oxo, thia, nitrile,nitro, formyl, mercapto, carboxy, carboxyalkyl, alkyl, haloalkyl,polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl,aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl,dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene,arylalkylidene, alkylcarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyl,arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl,aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl,aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl,diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy,heteroaryloxy, heteroaralkoxy, heterocyclyloxy, heterocyclylalkoxy,cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy,alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy,aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl,alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl,alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino,arylamino, diarylamino, alkylarylamino, alkylcarbonylamino,alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino,arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺(R²⁴)₃, —P(R²⁵)₂, —P(O)(R²⁵)₂, —OP(O)(R²⁵)₂,—N(R²⁴)C(O)R²⁶, dialkylphosphonyl, alkylarylphosphonyl,diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio,perfluoroalkylthio, carboxyalkylthio, thiocyano, isothiocyano,alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy,hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy,alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy,diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl,alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl,alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl,arylaminosulfonyl, diarylaminosulfonyl or alkylarylaminosulfonyl; or twoQ¹ groups, which substitute atoms in a 1, 2 or 1,3 arrangement, togetherform alkylenedioxy (i.e., —O—(CH₂)_(y)—O—), thioalkylenoxy (i.e.,—S—(CH₂)_(y)—O—) or alkylenedithioxy (i.e., —S—(CH₂)_(y)—S—) where y is1 or 2; or two Q¹ groups, which substitute the same atom, together formalkylene;

each R²⁴ is independently selected from the group consisting ofhydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyland heterocyclylalkyl;

each R²⁵ is independently selected from the group consisting of hydroxy,alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl and —N(R²⁷)R²⁸,

R²⁶ is alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or—N(R²⁷)R²⁸;

R²⁷ and R²⁸ are each independently hydrogen, alkyl, aralkyl, aryl,heteroaryl, heteroaralkyl or heterocyclyl,

or R²⁷ and R²⁸ together form alkylene, azaalkylene, oxaalkylene orthiaalkylene;

and each Q¹ is optionally substituted by one or more substituentsselected from Q²; where each Q² is independently halo, pseudohalo,hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto, carboxy,carboxyalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl,alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triplebonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl,trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triaryisilyl,alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl,heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl,aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl,aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl,diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy,heteroaryloxy, heteroaralkoxy, heterocyclyloxy, heterocyclylalkoxy,cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy,alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy,aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl,alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl,alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino,arylamino, diarylamino, alkylarylamino, alkylcarbonylamino,alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino,arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺(R²⁴)₃, —P(R²⁵)₂, —P(O)(R²⁵)₂, —OP(O)(R²⁵)₂,—N(R²⁴)C(O)R²⁶, dialkylphosphonyl, alkylarylphosphonyl,diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio,perfluoroalkylthio, carboxyalkylthio, thiocyano, isothiocyano,alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy,hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy,alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy,diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl,alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl,alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl,arylaminosulfonyl, diarylaminosulfonyl or alkylarylaminosulfonyl; or twoQ² groups, which substitute atoms in a 1,2 or 1,3 arrangement, togetherform alkylenedioxy (i.e., —O—(CH₂)_(y)—O—), thioalkylenoxy (i.e.,—S—(CH₂)_(y)—O—) or alkylenedithioxy (i.e., —S—(CH₂)_(y)—S—) where y is1 or 2; or two Q² groups, which substitute the same atom, together formalkylene,

where R²⁴, R²⁵, R²⁶, R²⁷ and R²⁸ are as defined above;

as a stereoisomer, racemate or mixture thereof; or as a pharmaceuticallyacceptable derivative thereof.

In one embodiment, R¹ is optionally substituted phenyl, and is selectedwith the proviso that it is not substituted at the 3 or 4 position with—C(OH)(CF₃)₂.

The groups R¹, R², R³, R⁴, and R⁵ are selected such that the resultingcompound has nuclear receptor modulation activity, such as in at leastone assay described herein, such as FXR antagonist or agonist activity,and, in certain embodiments, at an IC₅₀ or EC₅₀ of less than about 100μM. The FXR IC₅₀ or EC₅₀ values for the compounds provided herein are,in certain embodiments, less than about 50 μM, 25 μM, 10 μM, 1 μM, 100nM, 10 nM or 1 nM.

Also of interest are any pharmaceutically-acceptable derivatives,including salts, esters, enol ethers, enol esters, solvates, hydratesand prodrugs of the compounds described herein.Pharmaceutically-acceptable salts, include, but are not limited to,amine salts, such as but not limited to N,N′-dibenzylethylenediamine,chloroprocaine, choline, ammonia, diethanolamine and otherhydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine,N-benzylphenethylamine, 1-parachlorobenzyl-2-pyrrolidin-1′-ylmethyl-benzimidazole, diethylamine andother alkylamines, piperazine and tris(hydroxymethyl)aminomethane;alkali metal salts, such as but not limited to lithium, potassium andsodium; alkali earth metal salts, such as but not limited to barium,calcium and magnesium; transition metal salts, such as but not limitedto zinc, aluminum, and other metal salts, such as but not limited tosodium hydrogen phosphate and disodium phosphate; and also including,but not limited to, salts of mineral acids, such as but not limited tohydrochlorides and sulfates; and salts of organic acids, such as but notlimited to acetates, lactates, malates, tartrates, citrates, ascorbates,succinates, butyrates, valerates and fumarates.

Pharmaceutical compositions formulated for administration by anappropriate route and means containing effective concentrations of oneor more of the compounds provided herein, or pharmaceutically acceptablederivatives thereof, that deliver amounts effective for the treatment,prevention, or amelioration of one or more symptoms of diseases ordisorders that are modulated or otherwise affected by nuclear receptoractivity, including FXR and/or orphan nuclear receptor activity, or inwhich nuclear receptor activity, including FXR and/or orphan nuclearreceptor activity, is implicated, are also provided. The effectiveamounts and concentrations are effective for ameliorating any of thesymptoms of any of the diseases or disorders.

Methods for treatment, prevention, or amelioration of one or moresymptoms of diseases or disorders mediated by or in which nuclearreceptor activity, including FXR and/or orphan nuclear receptoractivity, is implicated, are provided. Such methods include methods oftreatment, prevention and amelioration of one or more symptoms ofhypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia,lipodystrophy, hyperglycemia, diabetes mellitus, dyslipidemia,atherosclerosis, gallstone disease, acne vulgaris, acneiform skinconditions, diabetes, Parkinson's disease, cancer, Alzheimer's disease,inflammation, immunological disorders, lipid disorders, obesity,conditions characterized by a perturbed epidermal barrier function,hyperlipidemia, cholestasis, peripheral occlusive disease, ischemicstroke, obesity, disease states associated with elevated cholesterollevels, including without limitation, coronary artery disease, anginapectoris, carotid artery disease, strokes, cerebral arteriosclerosis,disorders related to insulin resistance, including without limitation,xanthoma, glucose intolerance, an increase in plasma triglyceride and adecrease in high density lipoprotein cholesterol concentrations,hypertension, hyperuricemia, smaller density lipoprotein particles, andhigher circulating levels of plasminogen activator inhibitor-1,conditions of disturbed differentiation or excess proliferation of theepidermis or mucous membrane, or cardiovascular disorders, using one ormore of the compounds provided herein, or pharmaceutically acceptablederivatives thereof.

Methods of modulating the activity of nuclear receptors, including FXRand/or orphan nuclear receptors, using the compounds and compositionsprovided herein are also provided. The compounds and compositionsprovided herein are active in assays that measure the activity ofnuclear receptors, including FXR and/or orphan nuclear receptors,including the assays provided herein. These methods include inhibitingand up-regulating the activity of nuclear receptors, including FXRand/or orphan nuclear receptors.

Methods of reducing cholesterol levels in a subject in need thereof byadministration of one or more compounds or compositions provided hereinare also provided.

Methods of modulating cholesterol metabolism using the compounds andcompositions provided herein are provided.

Methods of treating, preventing, or ameliorating one or more symptoms ofdiseases or disorders which are affected by cholesterol, triglyceride,or bile acid levels by administration of one or more of the compoundsand compositions provided herein are also provided.

In practicing the methods, effective amounts of the compounds orcompositions containing therapeutically effective concentrations of thecompounds, which are formulated for systemic delivery, includingparenteral, oral, or intravenous delivery, or for local or topicalapplication, for the treatment of nuclear receptor, including FXR and/ororphan nuclear receptor, mediated diseases or disorders, or diseases ordisorders in which nuclear receptor activity, including FXR and/ororphan nuclear receptor activity, is implicated, including, but notlimited to, hypercholesterolemia, hyperlipoproteinemia,hypertriglyceridemia, lipodystrophy, hyperglycemia, diabetes mellitus,dyslipidemia, atherosclerosis, gallstone disease, acne vulgaris,acneiform skin conditions, diabetes, Parkinson's disease, cancer,Alzheimer's disease, inflammation, immunological disorders, lipiddisorders, obesity, conditions characterized by a perturbed epidermalbarrier function, hyperlipidemia, cholestasis, peripheral occlusivedisease, ischemic stroke, conditions of disturbed differentiation orexcess proliferation of the epidermis or mucous membrane, orcardiovascular disorders, are administered to an individual exhibitingthe symptoms of these diseases or disorders. The amounts are effectiveto ameliorate or eliminate one or more symptoms of the diseases ordisorders.

Articles of manufacture containing packaging material, a compound orcomposition, or pharmaceutically acceptable derivative thereof, providedherein, which is effective for modulating the activity of nuclearreceptors, including FXR and/or orphan nuclear receptors, or fortreatment, prevention or amelioration of one or more symptoms of nuclearreceptor, including FXR and/or orphan nuclear receptor, mediateddiseases or disorders, or diseases or disorders in which nuclearreceptor activity, including FXR and/or orphan nuclear receptoractivity, is implicated, within the packaging material, and a label thatindicates that the compound or composition, or pharmaceuticallyacceptable derivative thereof, is used for modulating the activity ofnuclear receptors, including FXR and/or orphan nuclear receptors, or fortreatment, prevention or amelioration of one or more symptoms of nuclearreceptor, including FXR and/or orphan nuclear receptor, mediateddiseases or disorders, or diseases or disorders in which nuclearreceptor activity, including FXR and/or orphan nuclear receptoractivity, is implicated, are provided.

DETAILED DESCRIPTION OF EMBODIMENTS A. Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art to which this invention belongs. All cited patents,applications, published applications and other publications areincorporated by reference in their entirety. In the event that there area plurality of definitions for a term herein, those in this sectionprevail unless stated otherwise.

As used herein, a nuclear receptor is a member of a superfamily ofregulatory proteins that are receptors for, e.g., steroids, retinoids,vitamin D and thyroid hormones. These proteins bind to cis-actingelements in the promoters of their target genes and modulate geneexpression in response to a ligand therefor. Nuclear receptors may beclassified based on their DNA binding properties. For example, theglucocorticoid, estrogen, androgen, progestin and mineralocorticoidreceptors bind as homodimers to hormone response elements (HREs)organized as inverted repeats. Another example are receptors, includingthose activated by retinoic acid, thyroid hormone, vitamin D₃, fattyacids/peroxisome proliferators and ecdysone, that bind to HREs asheterodimers with a common partner, the retinoid X receptor (RXR). Amongthe latter receptors are FXR.

As used herein, an orphan nuclear receptor is a gene product thatembodies the structural features of a nuclear receptor that wasidentified without any prior knowledge of their association with aputative ligand and/or for which the natural ligand is unknown. Underthis definition, orphan nuclear receptors include, without limitation,famesoid X receptor (FXR), liver X receptor (LXR α& β), retinoid Xreceptor (RXRα, β & γ), and peroxisome proliferator activator receptor(PPAR α, β, & γ) (see, Giguere (1999) Endocrine Reviews 20 (5):689-725).

As used herein, famesoid X receptor or FXR refers to all mammalian formsof such receptor including, for example, alternative splice isoforms andnaturally occurring isoforms (see, e.g. Huber et al (2002) Gene290:35-43). Representative FXR species include, without limitation ratFXR (GenBank Accession No. NM_(—)021745), mouse FXR (Genbank AccessionNo. NM_(—)009108), and human FXR (GenBank Accession No. NM_(—)005123).

As used herein, pharmaceutically acceptable derivatives of a compoundinclude salts, esters, enol ethers, enol esters, acetals, ketals,orthoesters, hemiacetals, hemiketals, acids, bases, solvates, hydratesor prodrugs thereof. Such derivatives may be readily prepared by thoseof skill in this art using known methods for such derivatization. Thecompounds produced may be administered to animals or humans withoutsubstantial toxic effects and either are pharmaceutically active or areprodrugs. Pharmaceutically acceptable salts include, but are not limitedto, amine salts, such as but not limited toN,N′-dibenzylethylenediamine, chloroprocaine, choline, ammonia,diethanolamine and other hydroxyalkylamines, ethylenediamine,N-methylglucamine, procaine, N-benzylphenethylamine,1-para-chlorobenzyl-2-pyrrolidin-1′-ylmethylbenzimidazole, diethylamineand other alkylamines, piperazine and tris(hydroxymethyl)aminomethane;alkali metal salts, such as but not limited to lithium, potassium andsodium; alkali earth metal salts, such as but not limited to barium,calcium and magnesium; transition metal salts, such as but not limitedto zinc; and other metal salts, such as but not limited to sodiumhydrogen phosphate and disodium phosphate; and also including, but notlimited to, salts of mineral acids, such as but not limited tohydrochlorides and sulfates; and salts of organic acids, such as but notlimited to acetates, lactates, malates, tartrates, citrates, ascorbates,succinates, butyrates, valerates and fumarates. Pharmaceuticallyacceptable esters include, but are not limited to, alkyl, alkenyl,alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl andheterocyclyl esters of acidic groups, including, but not limited to,carboxylic acids, phosphoric acids, phosphinic acids, sulfonic acids,sulfinic acids and boronic acids. Pharmaceutically acceptable enolethers include, but are not limited to, derivatives of formula C═C(OR)where R is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl,heteroaralkyl, cycloalkyl ar heterocyclyl. Pharmaceutically acceptableenol esters include, but are not limited to, derivatives of formulaC═C(OC(O)R) where R is hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, aralkyl, heteroaralkyl, cycloalkyl ar heterocyclyl.Pharmaceutically acceptable solvates and hydrates are complexes of acompound with one or more solvent or water molecules, or 1 to about 100,or 1 to about 10, or one to about 2, 3 or 4, solvent or water molecules.

As used herein, treatment means any manner in which one or more of thesymptoms of a disease or disorder are ameliorated or otherwisebeneficially altered. Treatment also encompasses any pharmaceutical useof the compositions herein, such as use for treating a nuclear receptor,including FXR and/or orphan nuclear receptor, mediated diseases ordisorders, or diseases or disorders in which nuclear receptor activity,including FXR and/or orphan nuclear receptor activity, is implicated.

As used herein, amelioration of the symptoms of a particular disorder byadministration of a particular compound or pharmaceutical compositionrefers to any lessening, whether permanent or temporary, lasting ortransient that can be attributed to or associated with administration ofthe composition.

As used herein, the IC₅₀ refers to an amount, concentration or dosage ofa particular test compound that achieves a 50% inhibition of a maximalresponse, such as modulation of FXR activity, in an assay that measuressuch response.

As used herein, EC₅₀ refers to a dosage, concentration or amount of aparticular test compound that elicits a dose-dependent response at 50%of maximal expression of a particular response that is induced, provokedor potentiated by the particular test compound.

As used herein, a prodrug is a compound that, upon in vivoadministration, is metabolized by one or more steps or processes orotherwise converted to the biologically, pharmaceutically ortherapeutically active form of the compound. To produce a prodrug, thepharmaceutically active compound is modified such that the activecompound will be regenerated by metabolic processes. Prodrugs of acompound of the invention may be prepared by modifying functional groupspresent in the compound of the invention in such a way that themodifications are cleaved, either in routine manipulation or in vivo, tothe parent compound of the invention. Prodrugs include compounds of theinvention wherein a hydroxy, amino or mercapto group is bonded to anygroup that, when the prodrug of the compound of the invention isadministered to a mammalian subject, cleaves to form a free hydroxy,free amino or free mercapto group, respectively. Examples of prodrugsinclude, but are not limited to, acetate, formate and benzoatederivatives of alcohol and amine functional groups in the compounds ofthe invention and the like.

The prodrug may be designed to alter the metabolic stability or thetransport characteristics of a drug, to mask side effects or toxicity,to improve the flavor of a drug or to alter other characteristics orproperties of a drug. By virtue of knowledge of pharmacodynamicprocesses and drug metabolism in vivo, those of skill in this art, oncea pharmaceutically active compound is known, can design prodrugs of thecompound (see, e.g., Nogrady (1985) Medicinal Chemistry. A BiochemicalApproach, Oxford University Press, New York, pages 388-392).

It is to be understood that the compounds provided herein may containchiral centers. Such chiral centers may be of either the (R) or (S)configuration, or may be a mixture thereof. Thus, the compounds providedherein may be enantiomerically pure, or be stereoisomeric ordiastereomeric mixtures. In the case of amino acid residues, suchresidues may be of either the L- or D-form. The configuration fornaturally occurring amino acid residues is generally L. When notspecified the residue is the L form. As used herein, the term “aminoacid” refers to α-amino acids which are racemic, or of either the D- orL-configuration. The designation “d” preceding an amino acid designation(e.g., dAla, dSer, dVal, etc.) refers to the D-isomer of the amino acid.The designation “dl” preceding an amino acid designation (e.g., dipip)refers to a mixture of the L- and D-isomers of the amino acid. It is tobe understood that the chiral centers of the compounds provided hereinmay undergo epimerization in vivo. As such, one of skill in the art willrecognize that administration of a compound in its (R) form isequivalent, for compounds that undergo epimerization in vivo, toadministration of the compound in its (S) form. When the compoundsdescribed herein contain olefinic double bonds or other centers ofgeometric asymmetry, and unless specified otherwise, it is intended thatthe compounds include both E and Z geometric isomers. Likewise, alltautomeric forms are also intended to be included.

As used herein, substantially pure means sufficiently homogeneous toappear free of readily detectable impurities as determined by standardmethods of analysis, such as thin layer chromatography (TLC), gelelectrophoresis, high performance liquid chromatography (HPLC) and massspectrometry (MS), used by those of skill in the art to assess suchpurity, or sufficiently pure such that further purification would notdetectably alter the physical and chemical properties, such as enzymaticand biological activities, of the substance. Methods for purification ofthe compounds to produce substantially chemically pure compounds areknown to those of skill in the art. A substantially chemically purecompound may, however, be a mixture of stereoisomers. In such instances,further purification might increase the specific activity of thecompound. Optically active (+) and (−), (R)- and (S)-, or (D)- and(L)-isomers may be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques, such as reverse phase HPLC.

As used herein, the nomenclature alkyl, alkoxy, carbonyl, etc. is usedas is generally understood by those of skill in this art.

As used herein, alkyl, alkenyl and alkynyl carbon chains, if notspecified, contain from 1 to 20 carbons, or 1 to 16 carbons, and arestraight or branched. Alkenyl carbon chains of from 2 to 20 carbons, incertain embodiments, contain 1 to 8 double bonds, and the alkenyl carbonchains of 2 to 16 carbons, in certain embodiments, contain 1 to 5 doublebonds. Alkynyl carbon chains of from 2 to 20 carbons, in certainembodiments, contain 1 to 8 triple bonds, and the alkynyl carbon chainsof 2 to 16 carbons, in certain embodiments, contain 1 to 5 triple bonds.Exemplary alkyl, alkenyl and alkynyl groups herein include, but are notlimited to, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl,sec-butyl, tert-butyl, isopentyl, neopentyl, tert-penytyl and isohexyl.As used herein, lower alkyl, lower alkenyl, and lower alkynyl refer tocarbon chains having from about 1 or about 2 carbons up to about 6carbons. As used herein, “alk(en)(yn)yl” refers to an alkyl groupcontaining at least one double bond and at least one triple bond.

As used herein, “cycloalkyl” refers to a saturated mono- or multicydicring system, in certain embodiments of 3 to 10 carbon atoms, in otherembodiments of 3 to 6 carbon atoms; cycloalkenyl and cycloalkynyl referto mono- or multicydic ring systems that respectively include at leastone double bond and at least one triple bond. Cycloalkenyl andcycloalkynyl groups may, in certain embodiments, contain 3 to 10 carbonatoms, with cycloalkenyl groups, in further embodiments, containing 4 to7 carbon atoms and cycloalkynyl groups, in further embodiments,containing 8 to 10 carbon atoms. The ring systems of the cycloalkyl,cycloalkenyl and cycloalkynyl groups may be composed of one ring or twoor more rings which may be joined together in a fused, bridged orspiro-connected fashion. “Cycloalk(en)(yn)yl” refers to a cycloalkylgroup containing at least one double bond and at least one triple bond.

As used herein, “substituted alkyl,” “substituted alkenyl,” “substitutedalkynyl,” “substituted cycloalkyl,” “substituted cycloalkenyl,” and“substituted cycloalkynyl” refer to alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl and cycloalkynyl groups, respectively, that are substitutedwith one or more substituents, in certain embodiments one to three orfour substituents, where the substituents are as defined herein,generally selected from Q¹ as defined above in the Summary of theInvention.

As used herein, “aryl” refers to aromatic monocyclic or multicyclicgroups containing from 6 to 19 carbon atoms. Aryl groups include, butare not limited to groups such as fluorenyl, substituted fluorenyl,phenyl, substituted phenyl, naphthyl and substituted naphthyl.

As used herein, “heteroaryl” refers to a monocyclic or multicyclicaromatic ring system, in certain embodiments, of about 5 to about 15members where one or more, in one embodiment 1 to 3, of the atoms in thering system is a heteroatom, that is, an element other than carbon,including but not limited to, nitrogen, oxygen or sulfur. The heteroarylgroup may be optionally fused to a benzene ring. Heteroaryl groupsinclude, but are not limited to, furyl, imidazolyl, pyrrolidinyl,pyrimidinyl, tetrazolyl, thienyl, pyridyl, pyrrolyl, N-methylpyrrolyl,quinolinyl and isoquinolinyl.

As used herein, a “heteroarylium” group is a heteroaryl group that ispositively charged on one or more of the heteroatoms.

As used herein, “heterocyclyl” refers to a monocyclic or multicyclicnon-aromatic ring system, in one embodiment of 3 to 10 members, inanother embodiment of 4 to 7 members, in a further embodiment of 5 to 6members, where one or more, in certain embodiments, 1 to 3, of the atomsin the ring system is a heteroatom, that is, an element other thancarbon, including but not limited to, nitrogen, oxygen or sulfur. Inembodiments where the heteroatom(s) is(are) nitrogen, the nitrogen isoptionally substituted with alkyl, alkenyl, alkynyl, aryl, heteroaryl,aralkyl, heteroaralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl,heterocyclylalkyl, acyl, guanidino, or the nitrogen may be quaternizedto form an ammonium group where the substituents are selected as above.

As used herein, “substituted aryl,” “substituted heteroaryl” and“substituted heterocyclyl” refer to aryl, heteroaryl and heterocyclylgroups, respectively, that are substituted with one or moresubstituents, in certain embodiments one to three or four substituents,where the substituents are as defined herein, generally selected from Q¹as defined above in the Summary of the Invention.

As used herein, “aralkyl” refers to an alkyl group in which one of thehydrogen atoms of the alkyl is replaced by an aryl group.

As used herein, “heteroaralkyl” refers to an alkyl group in which one ofthe hydrogen atoms of the alkyl is replaced by a heteroaryl group.

As used herein, “halo”, “halogen” or “halide” refers to F, Cl, Br or I.

As used herein, pseudohalides or pseudohalo groups are groups thatbehave substantially similar to halides. Such compounds can be used inthe same manner and treated in the same manner as halides. Pseudohalidesinclude, but are not limited to, cyanide, cyanate, thiocyanate,selenocyanate, trifluoromethoxy, and azide.

As used herein, “haloalkyl” refers to an alkyl group in which one ormore of the hydrogen atoms are replaced by halogen. Such groups include,but are not limited to, chloromethyl, trifluoromethyl and1-chloro-2-fluoroethyl.

As used herein, “haloalkoxy” refers to —OR in which R is a haloalkylgroup.

As used herein, “sulfinyl” or “thionyl” refers to —S(O)—. As usedherein, “sulfonyl” or “sulfuryl” refers to —S(O)₂—. As used herein,“sulfo” refers to —S(O)₂O—.

As used herein, “oxycarbonyl” or “carbonyloxy” refers to a divalentradical, —C(O)O—.

As used herein, “aminocarbonyl” refers to —C(O)NH₂.

As used herein, “alkylaminocarbonyl” refers to —C(O)N(H)R in which R isalkyl, including lower alkyl. As used herein, “dialkylaminocarbonyl”refers to —C(O)N(R)R in which R and R are independently alkyl, includinglower alkyl; “carboxamide” refers to groups of formula —N(R)C(O)R inwhich R and R are independently alkyl, including lower alkyl.

As used herein, “diarylaminocarbonyl” refers to —C(O)N(R)R′ in which Rand R′ are independently selected from aryl, including lower aryl, suchas phenyl.

As used herein, “arylalkylaminocarbonyl” refers to —C(O)N(R)R′ in whichone of R and R′ is aryl, including lower aryl, such as phenyl, and theother of R and R′ is alkyl, including lower alkyl.

As used herein, “arylaminocarbonyl” refers to —C(O)N(H)R in which R isaryl, including lower aryl, such as phenyl.

As used herein, “carboxy” refers to —C(O)OH.

As used herein, “alkoxycarbonyl” refers to —C(O)OR in which R is alkyl,including lower alkyl.

As used herein, “aryloxycarbonyl” refers to —C(O)OR in which R is aryl,including lower aryl, such as phenyl.

As used herein, “alkoxy” and “alkylthio” refer to —OR and —SR, in whichR is alkyl, including lower alkyl.

As used herein, “aryloxy” and “arylthio” refer to —OR and —OR, in whichR is aryl, including lower aryl, such as phenyl.

As used herein, “aralkoxy” refers to —OR in which R is aralkyl, such asbenzyl.

As used herein, “alkylene” refers to a straight, branched or cyclic, incertain embodiments straight or branched, divalent aliphatic hydrocarbongroup, in one embodiment having from 1 to about 20 carbon atoms, inanother embodiment having from 1 to 12 carbons. In a further embodimentalkylene includes lower alkylene. There may be optionally inserted alongthe alkylene group one or more oxygen, sulfur, including S(═O) andS(═O)₂ groups, or optionally substituted nitrogen atoms, including —NR—and —N⁺RR— groups, where the nitrogen substituent(s) is(are) alkyl,aryl, aralkyl, heteroaryl, heteroaralkyl or COR′, where R′ is alkyl,aryl, aralkyl, heteroaryl, heteroaralkyl, —OY or —NYY, where Y ishydrogen, alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl. Alkylenegroups include, but are not limited to, methylene (—CH₂—), ethylene(—CH₂CH₂—), propylene (—(CH₂)₃—), methylenedioxy (—O—CH₂—O—) andethylenedioxy (—O—(CH₂)₂—O—). The term “lower alkylene” refers toalkylene groups having 1 to 6 carbons. In certain embodiments, alkylenegroups are lower alkylene, including alkylene of 1 to 3 carbon atoms.

As used herein, “azaalkylene” refers to —(CRR)_(n)—NR—(CRR)_(m)—, wheren and m are each independently an integer from 0 to 4. As used herein,“oxaalkylene” refers to —(CRR)_(n)—O—(CRR)_(m)—, where n and m are eachindependently an integer from 0 to 4. As used herein, “thiaalkylene”refers to —(CRR)_(n)—S(CRR)_(m), —(CRR)_(n)—S(═O)—(CRR)_(m)—, and—(CRR)_(n)—S(═O)₂—(CRR)_(m)—, where n and m are each independently aninteger from 0 to 4.

As used herein, “alkenylene” refers to a straight, branched or cyclic,in one embodiment straight or branched, divalent aliphatic hydrocarbongroup, in certain embodiments having from 2 to about 20 carbon atoms andat least one double bond, in other embodiments 1 to 12 carbons. Infurther embodiments, alkenylene groups include lower alkenylene. Theremay be optionally inserted along the alkenylene group one or moreoxygen, sulfur or optionally substituted nitrogen atoms, where thenitrogen substituent is alkyl. Alkenylene groups include, but are notlimited to, —CH═CH—CH═CH— and —CH═CH—CH₂—. The term “lower alkenylene”refers to alkenylene groups having 2 to 6 carbons. In certainembodiments, alkenylene groups are lower alkenylene, includingalkenylene of 3 to 4 carbon atoms.

As used herein, “alkynylene” refers to a straight, branched or cyclic,in certain embodiments straight or branched, divalent aliphatichydrocarbon group, in one embodiment having from 2 to about 20 carbonatoms and at least one triple bond, in another embodiment 1 to 12carbons. In a further embodiment, alkynylene includes lower alkynylene.There may be optionally inserted along the alkynylene group one or moreoxygen, sulfur or optionally substituted nitrogen atoms, where thenitrogen substituent is alkyl. Alkynylene groups include, but are notlimited to, —C≡C—C≡C—, —C≡C— and —C≡C—CH₂—. The term “lower alkynylene”refers to alkynylene groups having 2 to 6 carbons. In certainembodiments, alkynylene groups are lower alkynylene, includingalkynylene of 3 to 4 carbon atoms.

As used herein, “alk(en)(yn)ylene” refers to a straight, branched orcyclic, in certain embodiments straight or branched, divalent aliphatichydrocarbon group, in one embodiment having from 2 to about 20 carbonatoms and at least one triple bond, and at least one double bond; inanother embodiment 1 to 12 carbons. In further embodiments,alk(en)(yn)ylene includes lower alk(en)(yn)ylene. There may beoptionally inserted along the alkynylene group one or more oxygen,sulfur or optionally substituted nitrogen atoms, where the nitrogensubstituent is alkyl. Alk(en)(yn)ylene groups include, but are notlimited to, —C═C—(CH₂)_(n)—C≡C—, where n is 1 or 2. The term “loweralk(en)(yn)ylene” refers to alk(en)(yn)ylene groups having up to 6carbons. In certain embodiments, alk(en)(yn)ylene groups have about 4carbon atoms.

As used herein, “cycloalkylene” refers to a divalent saturated mono- ormulticyclic ring system, in certain embodiments of 3 to 10 carbon atoms,in other embodiments 3 to 6 carbon atoms; cycloalkenylene andcycloalkynylene refer to divalent mono- or multicyclic ring systems thatrespectively include at least one double bond and at least one triplebond. Cycloalkenylene and cycloalkynylene groups may, in certainembodiments, contain 3 to 10 carbon atoms, with cycloalkenylene groupsin certain embodiments containing 4 to 7 carbon atoms andcycloalkynylene groups in certain embodiments containing 8 to 10 carbonatoms. The ring systems of the cycloalkylene, cycloalkenylene andcycloalkynylene groups may be composed of one ring or two or more ringswhich may be joined together in a fused, bridged or spiro-connectedfashion. “Cycloalk(en)(yn)ylene” refers to a cycloalkylene groupcontaining at least one double bond and at least one triple bond.

As used herein, “substituted alkylene,” “substituted alkenylene,”“substituted alkynylene,” “substituted cycloalkylene,” “substitutedcycloalkenylene,” and “substituted cycloalkynylene” refer to alkylene,alkenylene, alkynylene, cycloalkylene, cycloalkenylene andcycloalkynylene groups, respectively, that are substituted with one ormore substituents, in certain embodiments one to three or foursubstituents, where the substituents are as defined herein, generallyselected from Q¹ as defined above in the Summary of the Invention.

As used herein, “arylene” refers to a monocyclic or polycyclic, incertain embodiments monocyclic, divalent aromatic group, in oneembodiment having from 5 to about 20 carbon atoms and at least onearomatic ring, in another embodiment 5 to 12 carbons. In furtherembodiments, arylene includes lower arylene. Arylene groups include, butare not limited to, 1,2-, 1,3- and 1,4-phenylene. The term “lowerarylene” refers to arylene groups having 5 or 6 carbons.

As used herein, “heteroarylene” refers to a divalent monocyclic ormulticyclic aromatic ring system, in one embodiment of about 5 to about15 members where one or more, in certain embodiments 1 to 3, of theatoms in the ring system is a heteroatom, that is, an element other thancarbon, including but not limited to, nitrogen, oxygen or sulfur.

As used herein, “heterocyclylene” refers to a divalent monocyclic ormulticyclic non-aromatic ring system, in certain embodiments of 3 to 10members, in one embodiment 4 to 7 members, in another embodiment 5 to 6members, where one or more, including 1 to 3, of the atoms in the ringsystem is a heteroatom, that is, an element other than carbon, includingbut not limited to, nitrogen, oxygen or sulfur.

As used herein, “substituted arylene,” “substituted heteroarylene” and“substituted heterocyclylene” refer to arylene, heteroarylene andheterocyclylene groups, respectively, that are substituted with one ormore substituents, in certain embodiments one to three of foursubstituents, where the substituents are as defined herein, generallyselected from Q¹ as defined above in the Summary of the Invention.

As used herein, “alkylidene” refers to a divalent group, such as ═CR′R″,which is attached to one atom of another group, forming a double bond.Alkylidene groups include, but are not limited to, methylidene (═CH₂)and ethylidene (═CHCH₃). As used herein, “arylalkylidene” refers to analkylidene group in which either R′ or R″ is an aryl group.“Cycloalkylidene” groups are those where R′ and R″ are linked to form acarbocyclic ring. “Heterocyclylidene” groups are those where at leastone of R′ and R″ contain a heteroatom in the chain, and R′ and R″ arelinked to form a heterocyclic ring.

As used herein, “amido” refers to the divalent group —C(O)NH—.“Thioamido” refers to the divalent group —C(S)NH—. “Oxyamido” refers tothe divalent group —OC(O)NH—. “Thiaamido” refers to the divalent group—SC(O)NH—. “Dithiaamido” refers to the divalent group —SC(S)NH—.“Ureido” refers to the divalent group —HNC(O)NH—. “Thioureido” refers tothe divalent group —HNC(S)NH—.

As used herein, “semicarbazide” refers to —NHC(O)NHNH—. “Carbazate”refers to the divalent group —OC(O)NHNH—. “Isothiocarbazate” refers tothe divalent group —SC(O)NHNH—. “Thiocarbazate” refers to the divalentgroup —OC(S)NHNH—. “Sulfonylhydrazide” refers to the group —SO₂NHNH—.“Hydrazide” refers to the divalent group —C(O)NHNH—. “Azo” refers to thedivalent group —N═N—. “Hydrazinyl” refers to the divalent group —NH—NH—.

Where the number of any given substituent is not specified (e.g.,“haloalkyl”), there may be one or more substituents present. Forexample, “haloalkyl” may include one or more of the same or differenthalogens. As another example, “C₁₋₃alkoxyphenyl” may include one or moreof the same or different alkoxy groups containing one, two or threecarbons.

As used herein, the following terms have their accepted meaning in thechemical literature:

AcOH acetic add

Cbz benzyl carbamate

CDI carbonyl diimidazole

CHCl₃ chloroform

conc concentrated

DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

DCM dichloromethane

DME 1,2-dimethoxyethane

DMF N,N-dimethylformamide

DMSO dimethylsulfoxide

EtOAc ethyl acetate

EtOH ethanol (100%)

Et₂O diethyl ether

Hex hexanes

H₂SO₄ sulfuric acid

MeCN acetonitrile

MeOH methanol

Pd (0) palladium (0)

Pd/C palladium on activated carbon

PPh₃ triphenyl phosphine

TEA triethylamine

THF tetrahydrofuran

TFA trifluoroacetic acid

As used herein, the abbreviations for any protective groups, amino acidsand other compounds, are, unless indicated otherwise, in accord withtheir common usage, recognized abbreviations, or the IUPAC-IUBCommission on Biochemical Nomenclature (see, (1972) Biochem.11:942-944).

B. Quinazolinone Modulators of Nuclear Receptors

Compounds for use in compositions and methods for modulating theactivity of nuclear receptors are provided. In particular, compounds foruse in compositions and methods for modulating farnesoid X receptor(FXR) and/or orphan nuclear receptors, are provided.

In one embodiment, the compounds have formula (I), where R¹ is hydrogen,optionally substituted alkyl, optionally substituted aryl, or optionallysubstituted aralkyl. In another embodiment, R¹ is hydrogen, optionallysubstituted alkyl, aryl, or aralkyl. In another embodiment, R¹ ishydrogen, methyl, ethyl, propyl, 2-methoxyethyl, benzyl, or naphthyl.

In one embodiment, the compounds for use in the compositions and methodsprovided herein have formula (I) where R¹ is optionally substitutedphenyl. In another embodiment, the compounds have formula (II):

wherein:

n is an integer from 0 to 5;

m is an integer from 0 to 4;

each R^(1a) and R³ are independently selected from halo, pseudohalo,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkylalkyl, optionallysubstituted heterocyclylalkyl, —N(R¹²)R¹³, —OR¹⁴, —C(E)R¹⁵ where E is O,S or NR⁷, or —S(O)_(y)R¹⁶ where y is 0, 1 or 2, with the proviso thatR^(1a) is not 3- or 4-C(OH)(CF₃)₂;

or any two R^(1a) groups or R³ groups, which substitute adjacent carbonson the ring, together with atoms to which they are attached, formoptionally substituted cycloalkyl, optionally substituted heterocyclyl,optionally substituted heteroaryl, or optionally substituted aryl;

R², R⁴, R⁵ and R⁶ are selected from (a) and (b) as follows:

-   -   (a) R² and R⁶ are selected from (i) and (ii) as follows: (i) R²        and R⁶ are each independently hydrogen or optionally substituted        alkyl; or (ii) R² and R⁶ together form alkylene or alkenylene;    -   R⁴ and R⁵ are selected from (i) and (ii) as follows: (i) R⁴ and        R⁵ are each independently selected from hydrogen, optionally        substituted alkyl, optionally substituted alkenyl, optionally        substituted alkynyl, optionally substituted aryl, optionally        substituted heteroaryl, optionally substituted cycloalkyl,        optionally substituted heterocyclyl, optionally substituted        aralkyl, optionally substituted heteroaralkyl, optionally        substituted cycloalkylalkyl, optionally substituted        heterocyclylalkyl, —N(R⁸)R⁹, —OR⁷, S(O)_(j)R¹¹ where j is 1 or        2, —B(R²²)₂, —P(R²²)₂, —P(O)(R²²)₂, and —C(E)R²³ where E is        selected from O, S and NR⁷; or (ii) R⁴ and R⁵ together form        optionally substituted alkylene, optionally substituted        alkenylene, optionally substituted alkyleneoxyalkylene or        optionally substituted alkyleneazaalkylene;    -   (b) R² and R⁵, or R² and R⁴, or R⁶ and R⁵, or R⁸ and R⁴,        together form a 5, 6 or 7 membered optionally substituted        heterocyclyl group, or a 5 or 6 membered optionally substituted        heteroaryl group; and the remainder of R², R⁴, R⁵ and R⁶ are        each independently selected as in (i) above;

each R⁷ is independently selected from the group consisting of hydrogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkylalkyl, and optionallysubstituted heterocyclylalkyl;

R⁸ and R⁹ are each independently selected from hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkylalkyl, optionallysubstituted heterocyclylalkyl, —S(O)_(j)R¹⁰ where j is 1 or 2, and—C(M)R¹¹, where M is selected from O and S;

or R⁸ and R⁹ together form alkylene, alkenylene, alkyleneoxyalkylene oralkyleneazaalkylene;

each R¹⁰ is independently selected from the group consisting ofoptionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkylalkyl, and optionallysubstituted heterocyclylalkyl;

each R¹¹ is independently selected from the group consisting ofoptionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkylalkyl, optionallysubstituted heterocyclylalkyl, —OR¹⁰ and —N(R⁷)₂;

R¹² and R¹³ are each independently selected from hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkylalkyl, optionallysubstituted heterocyclylalkyl, —C(M)R¹⁷ where M is O or S, and—S(O)_(j)R¹⁴ where j is 1 or 2;

or R¹² and R¹³ together form alkylene, alkenylene, alkyleneoxyalkyleneor alkyleneazaalkylene;

R¹⁴ is hydrogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, optionally substituted aralkyl,optionally substituted heteroaralkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocyclylalkyl or —C(M)R¹⁷where m is O or S;

R¹⁵ is hydrogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, optionally substituted aralkyl,optionally substituted heteroaralkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocyclylalkyl, —OH, —OR¹⁹ or—N(R²⁰)R²¹;

R¹⁶ is hydrogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, optionally substituted aralkyl,optionally substituted heteroaralkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocyclylalkyl, —OH, —OR¹⁹ or—N(R²⁰)R²¹;

R¹⁷ is hydrogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, optionally substituted aralkyl,optionally substituted heteroaralkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocyclylalkyl, —OR¹⁹ or—N(R²⁰)R²¹;

R¹⁸ is optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted cycloalkyl, optionallysubstituted heterocyclyl, optionally substituted aralkyl, optionallysubstituted heteroaralkyl, optionally substituted cycloalkylalkyl,optionally substituted heterocyclylalkyl, —OR¹⁹ or —N(R²⁰)R²¹;

R¹⁹ is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl orheteroaralkyl;

R²⁰ and R²¹ are each independently selected from hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl,heterocyclylalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl,

or R²⁰ and R²¹ together form alkylene, alkenylene oralkyleneoxyalkylene;

each R²² is independently selected from the group consisting ofoptionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkylalkyl, optionallysubstituted heterocyclylalkyl, —OR⁷ and —N(R⁷)₂;

R²³ is hydrogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, optionally substituted aralkyl,optionally substituted heteroaralkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocyclylalkyl, —OR¹⁰,—N(R⁷)₂, —N(R⁷)N(R⁷)₂;

wherein each of the above R¹-R²³ groups, when substituted, aresubstituted with one or more substituents each independently selectedfrom Q¹, where Q¹ is halo, pseudohalo, hydroxy, oxo, thia, nitrile,nitro, formyl, mercapto, carboxy, carboxyalkyl, alkyl, haloalkyl,polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl,aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl,dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene,arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl,aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl,arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl,arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy,heterocyclyloxy, heterocyclylalkoxy, cycloalkoxy, perfluoroalkoxy,alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy,aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy,aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy,dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy,diarylaminocarbonyloxy, guanidino, isothioureido, amidino, alkylamidino,arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl,arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl,alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino,arylamino, diarylamino, alkylarylamino, alkylcarbonylamino,alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino,arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺(R²⁴)₃, —P(R²⁵)₂, —P(O)(R²⁵)₂, —OP(O)(R²⁵)₂,—N(R²⁴)C(O)R²⁶, dialkylphosphonyl, alkylarylphosphonyl,diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio,perfluoroalkylthio, carboxyalkylthio, thiocyano, isothiocyano,alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy,hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy,alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy,diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl,alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl,alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl,arylaminosulfonyl, diarylaminosulfonyl or alkylarylaminosulfonyl; or twoQ¹ groups, which substitute atoms in a 1, 2 or 1,3 arrangement, togetherform alkylenedioxy (i.e., —O—(CH₂)_(y)—O—), thioalkylenoxy (i.e.,—S—(CH₂)_(y)—O—) or alkylenedithioxy (i.e., —S(CH₂)_(y)—S—) where y is 1or 2; or two Q¹ groups, which substitute the same atom, together formalkylene;

each R²⁴ is independently selected from the group consisting ofhydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyland heterocyclylalkyl;

each R²⁵ is independently selected from the group consisting of hydroxy,alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl and —N(R²⁷)R²⁸,

R²⁵ is alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or—N(R²⁷)R²⁸;

R²⁷ and R²⁸ are each independently hydrogen, alkyl, aralkyl, aryl,heteroaryl, heteroaralkyl or heterocyclyl,

or R²⁷ and R²⁸ together form alkylene, azaalkylene, oxaalkylene orthiaalkylene;

and each Q¹ is optionally substituted by one or more substituentsselected from Q²; where each Q² is independently halo, pseudohalo,hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto, carboxy,carboxyalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl,alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triplebonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl,trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl,alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl,heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl,aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl,aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl,diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy,heteroaryloxy, heteroaralkoxy, heterocyclyloxy, heterocyclylalkoxy,cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy,alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy,aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl,alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl,alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino,arylamino, diarylamino, alkylarylamino, alkylcarbonylamino,alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino,arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺(R²⁴)₃, —P(R²⁵)₂, —P(O)(R²⁵)₂, —OP(O)(R²⁵)₂,—N(R²⁴)C(O)R²⁶, dialkylphosphonyl, alkylarylphosphonyl,diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio,perfluoroalkylthio, carboxyalkylthio, thiocyano, isothiocyano,alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy,hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy,alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy,diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl,alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl,alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl,arylaminosulfonyl, diarylaminosulfonyl or alkylarylaminosulfonyl; or twoQ² groups, which substitute atoms in a 1, 2 or 1,3 arrangement, togetherform alkylenedioxy (i.e., —O—(CH₂)_(y)—O—), thioalkylenoxy (i.e.,—S—(CH₂)_(y)—O—) or alkylenedithioxy (i.e., —S—(CH₂)_(y)—S—) where y is1 or 2; or two Q² groups, which substitute the same atom, together formalkylene,

where R²⁴, R²⁵R²⁶, R²⁷ and R²⁸ are as defined above;

as a stereoisomer, racemate or mixture thereof; or as a pharmaceuticallyacceptable derivative thereof.

In another embodiment, any two R^(1a) groups or R³ groups, whichsubstitute adjacent carbons on the ring, together with atoms to whichthey are attached, form optionally substituted alkylene, optionallysubstituted alkenylene, optionally substituted alkylenedioxy, optionallysubstituted thioalkylenoxy, or optionally substituted alkylenedithioxy.

In one embodiment, R^(1a) is not —C(OH)(CF₃)₂. In another embodiment, R⁶is hydrogen. In another embodiment, n is 0, 1 or 2. In anotherembodiment, m is 1.

In another embodiment, the compounds are of formula (II), where eachR^(1a) is independently halo, pseudohalo, optionally substituted alkyl,optionally substituted alkoxy, optionally substituted aryl, optionallysubstituted dialkylamino, optionally substituted aralkoxy, hydroxy,optionally substituted heteroaryl, optionally substituted heterocyclylor optionally substituted cycloalkyl.

In another embodiment, each R^(1a) is independently halo; pseudohalo;alkyl; haloalkyl; alkoxy; haloalkoxy; heterocyclylalkoxy; alkoxyalkoxy;aryl; aryl substituted with alkyl, halo, —C(O)OH, alkoxy, pseudohalo or—C(O)O-alkyl; dialkylamino; aralkoxy; hydroxy; heteroaryl; heterocyclyl;or cycloalkyl.

In another embodiment, each R^(1a) is independently chloro, fluoro,ethyl, methyl, methoxy, bromo, cyano, phenyl, tert-butyl,trifluoromethoxy, dimethylamino, trifluoromethyl, benzyloxy, hydroxy,2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-chlorophenyl,3-chlorophenyl, 4-chlorophenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, ethoxy, isopropoxy, butoxy, isobutoxy,2-(N-morpholino)ethoxy, 2-methoxyethoxy, 4-cyanophenyl, 2-thienyl,3-thienyl, 3-methoxycarbonylphenyl, 4-methoxycarbonylphenyl,3-carboxyphenyl, N-pyrrolidinyl, or N-morpholinyl.

In another embodiment, R² is hydrogen or optionally substituted alkyl,and R⁶ is hydrogen. In another embodiment, R² is hydrogen or alkyl. Inanother embodiment, R² is hydrogen, methyl or ethyl.

In another embodiment, each R³ is independently optionally substitutedalkyl, halo, pseudohalo, optionally substituted alkoxy, hydroxy,optionally substituted aralkoxy, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, oroptionally substituted cycloalkyl.

In another embodiment, each R³ is independently alkyl; halo; alkoxy;hydroxy; aralkoxy; aryl; heteroaryl; alkoxycarbonylalkoxy; arylsubstituted with alkyl, halo, pseudohalo, alkoxy, —C(O)OH or—C(O)O-alkyl; or heterocyclyl.

In another embodiment, each R³ is independently methyl, chloro, methoxy,hydroxy, bromo, ethoxy, isopropoxy, isobutoxy, butoxy, benzyloxy,ethoxycarbonylmethoxy, phenyl, 2-thienyl, 3-thienyl, 2-methylphenyl,3-methylphenyl, 4-methylpheny, 2-chlorophenyl, 3-chlorophenyl,4-chlorophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-carboxyphenyl,N-pyrrolidinyl, N-morpholinyl, 3-methoxycarbonylphenyl,4-methoxycarbonylphenyl, 3-carboxyphenyl, 4-cyanophenyl, or piperidinyl.

In another embodiment, one of R⁴ and R⁵ is —SO₂— (optionally substitutedaryl). In another embodiment, one of R⁴ and R⁵ is —SO₂— (optionallysubstituted phenyl).

In another embodiment, the compounds for use in the compositions andmethods provided herein have formula (III):

where R^(1a), R², R³, R⁴, R⁶, n and m are as defined above; t is aninteger from 0 to 5; each R^(5a) is independently optionally substitutedalkyl, optionally substituted alkoxy, optionally substituted heteroaryl,optionally substituted aryl, optionally substituted heterocyclyl, halo,pseudohalo; or any two R^(5a) substituents, which substitute adjacentatoms on the ring, together form a optionally substituted cycloalkyl,optionally substituted heterocyclyl, optionally substituted aryl, oroptionally substituted heteroaryl ring having 5 or 6 members in the ringand where the heteroatoms, if present, are selected from O, S andoptionally substituted N; where R^(5a), when substituted, is substitutedwith one or more, in one embodiment one to five, in another embodimentone, two or three, substituents each independently selected from Q¹, asdefined above.

In another embodiment, any two R^(5a) substituents, which substituteadjacent atoms on the ring, together form —N═C(R²⁹)—C(R²⁹)═C(R²⁹)— or—C(R²⁹)═C(R²⁹)—C(R²⁹)═C(R²⁹)—, where each R²⁹ is independently hydrogen,halo, pseudohalo, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocyclyl, optionally substitutedaryl, optionally substituted heteroaryl, optionally substituted aralkyl,or optionally substituted heteroaralkyl;

where R^(5a) and R²⁹, when substituted, are substituted with one ormore, In one embodiment one to five, in another embodiment one, two orthree, substituents each independently selected from Q¹, as definedabove.

In another embodiment, the compounds have formula (III), where eachR^(5a) is independently alkyl, alkoxy, haloalkoxy, heterocyclyl,heteroaryl, halo, haloalkyl, aryl or pseudohalo; or any two R^(5a)groups, which substitute adjacent carbons on the ring, together form—N═C(H)—C(H)═CH— or —C(H)═C(H)—C(H)═C(H)—.

In another embodiment, each R^(5a) is independently tert-butyl, methoxy,methyl, trifluoromethoxy, 2-thienyl, fluoro, chloro, trifluoromethyl,phenyl, cyano, n-propyl, 1,1-dimethylpropyl, isopropyl, butoxy orn-butyl; or any two R^(5a) groups, which substitute adjacent carbons onthe ring, together form —N═C(H)—C(H)═CH— or —C(H)═C(H)—C(H)═C(H)—.

In another embodiment, the compounds have formula (III) where R⁴ ishydrogen, optionally substituted alkyl, optionally substituted aralkyl,or optionally substituted heteroaralkyl. In another embodiment, R⁴ ishydrogen, alkyl, aralkyl or heteroaralkyl. In another embodiment, R⁴ ishydrogen, methyl, 2-methoxy-1-ethyl, propyl, isobutyl, butyl, pentyl,isopentyl, hexyl, benzyl, phenethyl or 2-thienylmethyl.

In another embodiment, one R^(5a) group is 4-tert-butyl or 4-isopropyl.

In another embodiment, the compounds of formula (II) are the compoundsof formula (III):

wherein:

n is an integer from 0 to 5;

m is an integer from 0 to 4;

t is an integer from 0 to 5;

each R^(1a) is independently selected from the group consisting ofalkyl, hydroxy, alkoxy, alkoxyalkoxy, aralkoxy, amino, alkylamino,dialkylamino, halo, haloalkyl, haloalkoxy, cyano, carboxy,alkoxycarbonyl, alkoxycarbonylalkoxy, heteroaryl, heterocyclyl,heterocyclylalkoxy, and aryl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, alkoxy, halo,cyano, carboxy, cyano, and alkoxycarbonyl);

R² is hydrogen or alkyl′

each R³ is independently selected from the group consisting of alkyl,alkoxy, halo, hydroxy, aralkoxy, alkoxycarbonylalkoxy, aryl (optionallysubstituted by one or more substituents independently selected from thegroup consisting of alkyl, halo, alkoxy, carboxy, alkoxycarbonyl, cyano,heteroaryl and heterocyclyl;

R⁴ is hydrogen or alkyl;

each R^(5a) is independently selected from the group consisting ofalkyl, alkoxy, halo, alkylcarbonyl, haloalkyl, haloalkoxy, aryl, cyano,carboxy, alkoxycarbonyl, nitro, and —N(R²⁴)C(O)R²⁶;

or two adjacent R^(5a) groups form an aryl, heterocyclyl or heteroaryl;and

R⁶ is hydrogen or alkyl.

Of this group of compounds, a preferred subgroup are those compoundswherein m is 0 or 1, n is 1 and each R^(1a) is alkoxy.

Another preferred subgroup are those compounds wherein m is 0 or 1, n is1, 2 or 3 and each R^(1a) is selected from alkyl.

Another preferred subgroup are those compounds wherein m is 0 or 1, n is1 and each R^(1a) is independently selected from halo, haloalkyl,haloalkoxy, and cyano.

Another preferred subgroup are those compounds wherein m is 0 or 1, n is0 or 1 and each R^(1a) is selected from carboxy, dialkylamino, hydroxy,alkoxyalkoxy, alkoxycarbonylalkoxy, aralkoxy, and heterocyclylalkoxy.

Another preferred subgroup are those compounds wherein m is 0 or 1, n is1 and R^(1a) is selected from optionally substituted aryl, heterocyclyland heteroaryl. Even more preferred in this subgroup are those compoundswherein the aryl group is phenyl.

In another embodiment, the compounds for use in the compositions andmethods provided herein have formula (IV):

where R^(1a), R², R³, R⁴, R⁶, R^(5a), m and n are selected as above; uis an integer from 0 to 4; and R^(5b) is tert-butyl or isopropyl. Inanother embodiment, R^(5b) is tert-butyl. In another embodiment, R^(5b)is isopropyl.

In another embodiment of formula (I), one of R⁴ and R⁵ is —C(O)—(optionally substituted aryl). In another embodiment, one of R⁴ and R⁵is —C(O)— (optionally substituted phenyl). In another embodiment, thecompounds for use in the compositions and methods provided herein haveformula (V):

where R^(1a), R², R³, R⁴, R⁶, R^(5a), t, n and m are as defined above.

In another embodiment, the compounds have formula (V) where each R^(1a)is independently halo, optionally substituted alkyl, or optionallysubstituted alkoxy, where the substituents, when present, are selectedfrom Q¹, as defined above. In another embodiment, each R^(1a) isindependently alkoxy, alkyl or halo. In another embodiment, each R^(1a)is independently methoxy, methyl, chloro or fluoro.

In another embodiment, the compounds have formula (V) where R² ishydrogen or optionally substituted alkyl, where the substituents, whenpresent, are selected from Q¹, as defined above. In another embodiment,R² is hydrogen or alkyl. In another embodiment, R² is hydrogen ormethyl.

In another embodiment, the compounds have formula (V) where each R³ isindependently hydrogen or optionally substituted alkoxy, where thesubstituents, when present, are selected from Q¹, as defined above. Inanother embodiment, each R³ is independently hydrogen or alkoxy. Inanother embodiment, each R³ is independently hydrogen or methoxy.

In another embodiment, the compounds have formula (V) where R⁴ isoptionally substituted alkyl, where the substituents, when present, areselected from Q¹, as defined above. In another embodiment, R⁴ is alkyl.In another embodiment, R⁴ is butyl or methyl.

In another embodiment, the compounds have formula (V) where R⁶ ishydrogen.

In another embodiment, the compounds have formula (V) where each R^(5a)is independently optionally substituted alkyl, where the substituents,when present, are selected from Q¹, as defined above. In anotherembodiment, each R^(5a) is alkyl. In another embodiment, R^(5a) istert-butyl.

In another embodiment, the compounds of formula (II) are the compoundsof formula (V):

wherein:

m is an integer from 0 to 4;

n is an integer from 0 to 5;

t is an integer from 0 to 5;

each R^(1a) is selected from the group consisting of alkyl, alkoxy,aralkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, anddialkylamino;

R², R⁴ and R⁶ are each independently hydrogen or alkyl;

each R³ is independently selected from the group consisting of alkyl,alkoxy, and halo; and

each R^(5a) is independently selected from the group consisting ofalkyl, alkoxy, alkoxycarbonyl, halo, and aryl

or two adjacent R^(5a) groups form an aryl, heterocyclyl or heteroaryl.

Of this group of compounds, a preferred subgroup are those compoundswherein m is 0 or 1, n is 1 and each R^(1a) is alkoxy.

Another preferred subgroup are those compounds wherein m is 0 or 1, n is1, 2 or 3 and each R^(1a) is selected from alkyl.

Another preferred subgroup are those compounds wherein m is 0 or 1, n is0 or 1 and each R^(1a) is independently selected from dialkylamino,aralkoxy, halo, haloalkyl and haloalkoxy.

In another embodiment, the compounds have formula (I) where one of R⁴and R⁵ is —C(O)— (optionally substituted alkyl), where the substituents,when present, are selected from Q¹, as defined above, and the other ofR⁴ and R⁵ is selected from hydrogen and optionally substituted alkyl,where the substituents, when present, are selected from Q¹, as definedabove. In another embodiment, one of R⁴ and R⁵ is —C(O)-alkyl, and theother is alkyl. In another embodiment, one of R⁴ and R⁵ is —C(O)-octyl,and the other is methyl or butyl.

In another embodiment, the compounds have formula (I) where one of R⁴and R⁵ is —C(O)—N(R⁸)R⁹, where R⁸ and R⁹ are independently selected fromhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted cycloalkyl, optionallysubstituted heterocyclyl, optionally substituted aralkyl, optionallysubstituted heteroaralkyl, optionally substituted cycloalkylalkyl, andoptionally substituted heterocyclylalkyl; or R⁸ and R⁹ together formalkylene, alkenylene, alkyleneoxyalkylene or alkyleneazaalkylene; whereR⁸ and R⁹ are each independently unsubstituted or substituted with oneor more, in one embodiment one to five, in another embodiment one, twoor three, substituents each independently selected from Q¹, as definedabove, and the other of R⁴ and R⁵ is selected from hydrogen andoptionally substituted alkyl, where the substituents, when present, areselected from Q¹, as defined above. In another embodiment, the other ofR⁴ and R⁵ is alkyl. In another embodiment, the other of R⁴ and R⁵ ismethyl or butyl.

In another embodiment, the compounds have formula (I) where R⁸ and R⁹are each independently selected from hydrogen, optionally substitutedcycloalkyl, and optionally substituted aryl. In another embodiment, R⁸is hydrogen. In another embodiment, R⁹ is cyclohexyl, 4-nitrophenyl,2-methoxyphenyl, 3-cyanophenyl, 3,4 dichlorophenyl,2,6-diisopropylphenyl, 2-methylphenyl, 2-trifluoromethylphenyl,2-fluorophenyl, 3-fluorophenyl, 3-methylphenyl, 3-chlorophenyl,2,6-dimethylphenyl or 3-trifluoromethylphenyl.

In another embodiment, the compounds have formula (I) where R⁴ and R⁵together form optionally substituted alkyleneazaalkylene, where thesubstituents, if present, are each independently selected from Q¹, asdefined above. In one embodiment, there are one, two or three Q¹substituents. In another embodiment, R⁴ and R⁵ together form—CH₂—C(H)(Me)—N(R³⁰)—CH₂—CH₂—, where R³⁰ is optionally substitutedheteroarylcarbonyl, optionally substituted alkylcarbonyl, optionallysubstituted arylcarbonyl, optionally substituted arylsulfonyl,optionally substituted alkylaminocarbonyl, or optionally substitutedarylaminocarbonyl.

In another embodiment, R³⁰ is 2-thienylcarbonyl, butyryl,4-fluorobenzoyl, benzyloxyacetyl, diphenylacetyl, 4-nitrobenzoyl,2,5-dichlorobenzenesulfonyl, tert-butylaminocarbonyl,4-tert-butylphenylsulfonyl, phenylaminocarbonyl,2,3-dichlorophenylaminocarbonyl or 3,4-methylenedioxybenzoyl.

In another embodiment, the compounds for use in the compositions andmethods provided herein have any of formulae I-V, where Q² is halo,pseudohalo, aralkoxy or nitro; or any two Q² groups, which substituteadjacent carbons, together form alkylenedioxy. In another embodiment, Q²is nitro, fluoro, benzyloxy or chloro; or two Q² groups, whichsubstitute adjacent carbons, together form methylenedioxy.

Of the compounds disclosed herein, the most preferred compounds arethose selected from the group consisting of the following:

-   4-tert-butyl-N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;-   4-tert-butyl-N-{1-[6-methoxy-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;-   4-tert-butyl-N-{1-[3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;-   4-tert-butyl-N-{1-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;-   4-tert-butyl-N-methyl-N-[1-(4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]benzenesulfonamide;-   4-tert-butyl-N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;-   4-tert-butyl-N-{1-[3-(4-methoxyphenyl)-6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;-   4-tert-butyl-N-{1-[6-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;-   N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-isopropyl-N-methylbenzenesulfonamide;    and-   biphenyl-4-sulfonic acid    {1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide.

C. Preparation of the Compounds

Starting materials in the synthesis examples provided herein are eitheravailable from commercial sources or via literature procedures. Allcommercially available compounds were used without further purificationunless otherwise indicated. CDCl₃ (99.8% D, Cambridge IsotopeLaboratories) was used in all experiments as indicated. Proton (¹H)nuclear magnetic resonance (NMR) spectra were recorded on a BrukerAvance 400 MHz NMR spectrometer. Significant peaks are tabulated andtypically include: number of protons, and multiplicity (s, singlet; d,double; t, triplet; q, quartet; m, multiplet; br s, broad singlet).Chemical shifts are reported as parts per million (δ) relative totetramethylsilane. Low resolution mass spectra (MS) were obtained aselectrospray ionization (ESI) mass spectra, which were recorded on aPerkin-Elmer SCIEX HPLC/MS instrument using reverse-phase conditions(acetonitrile/water, 0.05% trifluoroacetic acid). Flash chromatographywas performed using Merck Silica Gel 60 (230-400 mesh) followingstandard protocol (Still et al. (1978) J. Org. Chem. 43,2923).

Substituted methyl-anthranilates are commercially available or can besynthetically obtained from commercially available starting materials,using standard literature protocols (Scheme 1) in which R is typically ahalogen, alkyl, or alkoxy.

N-acyl methyl anthranilates 3 are prepared by treating methylanthranilate 1 with an acid chloride 2 in which R₁ is typically alkyl,aryl, or heteroaryl (Scheme 2).

Acid chlorides are commercially available and/or can be prepared usingstandard methods found in literature. R₁ is typically 1-chloroethyl or aproduct derived from protected amino acids, e.g., N-CBZ glycine. In thecase where protected amino acids are used alternative acylationconditions were required (Yu, Melvin, et al. (1992) J. Med. Chem.35:2534-2542). For example, the protected amino acid 4 is treated withcarbonyl diimidazole (CDI) followed by subsequent treatment of asubstituted methyl anthranilate 1 to yield the N-acyl methylanthranilate 3 (Scheme 3). Once again, chemical diversity is realized byvarying R and R₁ as previously described.

The quinazolinone core 5 was prepared by acylating an amine with theN-acyl anthranilic acid followed by a tandem cyclodehydration viathermolysis (Rao et al. (1985) J. Indian Chem.:234-237. N-Acylanthranilic acid 3 was treated with phosphorous trichloride and anamine, under refluxing conditions, to afford the desired quinazolinones5 (Scheme 4) in which R₂ typically includes an aryl (aniline),heteroaryl, or primary amines. When 3 possesses a protected aminoappendage alternative conditions were required to generate the core (6)(Yu et al. (1992) J. Med. Chem. 35:2534-2542).

For example, compound 3 was treated with carbonyl diimidazole in whichthe resulting activated acid was treated with an amine (R₂—NH₂) underrefluxing conditions to yield the quinazolinone 6 (Scheme 5).

The protected amino appendage was then deprotected using standardconditions found in literature reference (Greene et al. ProtectiveGroups in Organic Synthesis, 3rd Ed. (John Wiley, NY (1999))). Forexample, compound 5 was subjected to hydrogenation conditions to yield afree amine 7 (Scheme 6). Subsequently, the free amine was treated with anumber of different electrophiles (R₃) to yield a diverse set ofquinazolinone analogs (8) in which R₃ is typically an amide orsulfonamide but not limited to these groups. Additional electrophilesinclude carboxylic acids and derivatives thereof, sulfonyl chlorides,isocyanates, alkyl halides, aldehydes, ketones, and chloroformates.

Alternatively, when R₁ is a substituted 1-chloroalkyl (9) variousnucleophiles were introduced i.e. amines, alcohols, cuprates etc. Forexample when 1′-chloro ethyl quinazolinone 9 was treated with an amineunder the appropriate conditions, quinazolinone 10 was realized (Scheme7A). Subsequently, when R₄ is equal to hydrogen, 10 was treated withvarious electrophiles to yield compounds like 11, in which R₄ istypically an amide or sulfonamide, but not limited to (Scheme 7B).Additional electrophiles include carboxylic acids and derivativesthereof, sulfonyl chlorides, isocyanates, alkyl halides, aldehydes,ketones, and chloroformates.

An aryl bromide containing quinazolinone (12) can be further manipulatedwith the addition of diverse structural modifications using standardC—C, C—N, and C—O bond forming reactions. The purpose of this was togain entry into a diverse set of analogs that were not accessiblethrough previously described methods. For example, a bromo-substitutedheterocycle can be manipulated using standard transitions metalchemistries to introduce a large array of diverse functionalities thatare otherwise difficult to obtain using alternative methods (Hegedus,Louis, S. Transition Metals in the Synthesis of Complex OrganicMolecules, University Science Books: Mill Valley, Calif. (1994)).Quinazolinone 12 was treated with Pd (0) and a phosphorous ligand in thepresence of the appropriate coupling partner (R₅) to yield a new seriesof quniazolinone analogs similar to 13 (Scheme 8). A typical (R₅)reagent would include boronic acids, (esters), amines, amides,mono-substituted alkynes, alcohols, or organotin reagents. Thesereagents are typically aryl, heteroaromatic, and alkyl in nature. Inaddition, these monomeric reagents are commercially available and/or canbe synthesized using known literature methodologies.

Similarly, compound 14 was modified using the same chemistries describedabove. The conditions and reagents used to modify the N-arylquinazolinones 14 are identical to those previously described. Compound14 was treated with Pd (0) and a phosphorous ligand in the presence ofan appropriate monomer (R₅) to yield N-aryl substituted quinazolinoneslike compound 15 (Scheme 9). A typical (R₅) monomer would includeboronic acids, amines, amides, mono-substituted alkynes, alcohols, ororganotin reagents. These monomers are typically aryl, heteroaromatic,and alkyl in nature. In addition, these monomeric reagents arecommercially available and/or can be synthesized using known literaturemethodologies.

Additional modifications were made to the quinazolinone core bydemethylating the methoxyphenyl ether of quinazolinone 16 to reveal aphenol 17 as handle for a point of diversity. Methoxy phenyl ethers aretypically demethylated using a variety of literature methods (McOmie, J.F. W., West, D. E. Org. Synth., Collect. Vol. V, 412 (1973): Jung, M.E., Lyster, M. A., J. Org. Chem., 42, 3761 (1977)). For example, when 16is treated with boron tribromide the exclusive formation of phenol 17was observed (Scheme 10). Similarly, the methoxy substituted N-arylquinazolinone 18 was manipulated using the same protocol outlined aboveto yield compound 19 (Scheme 11).

Treatment of a phenol with a variety of electrophiles establishes yetanother avenue for diversity to be introduced that was not easilyaccessible with other methodologies. For example the phenol 17 wastreated with various electrophiles, i.e. alkyl halides, isocyanates andacid chlorides to yield ethers, carbamates and esters respectively.Additionally, the phenol 17 was converted to various ethers 20 byutilizing the Mitsunobu reaction (Mitsunobu, O.; Yamada, M. Bull. Chem.Soc. Jpn., 1967, 40,2380; Canp, D.; Jenkins, I. D. Aust J. Chem., 1988,41, 1835). Compound 17 was treated with triphenyl phosphine, alcohol(R₅OH) and diisopropyl azodicarboxylate (DIAD) to afford quinazolinone20 (Scheme 12). Typical alcohols that were used include primary andsecondary aliphatic alcohols. However, alcohols containing otherfunctionalities were also used, e.g. ethyl glycolate.

Similarly, compound 19 could be converted in an identical manner asdescribed above to achieve analogs similar to 21. A large array ofdiverse functionalities can be introduced that were otherwise difficultto obtain using alternative methods (Scheme 13).

D. Formulation of Pharmaceutical Compositions

The pharmaceutical compositions provided herein contain therapeuticallyeffective amounts of one or more of the nuclear receptor activitymodulators provided herein that are useful in the prevention, treatment,or amelioration of one or more of the symptoms of diseases or disordersassociated with nuclear receptor activity, including FXR and/or orphannuclear receptor activity. Such diseases or disorders include, but arenot limited to, hypercholesterolemia, hyperlipoproteinemia,hypertriglyceridemia, lipodystrophy, hyperglycemia, diabetes mellitus,dyslipidemia, atherosclerosis, gallstone disease, acne vulgaris,acneiform skin conditions, diabetes, Parkinson's disease, cancer,Alzheimer's disease, inflammation, immunological disorders, lipiddisorders, obesity, conditions characterized by a perturbed epidermalbarrier function, hyperlipidemia, cholestasis, peripheral occlusivedisease, ischemic stroke, conditions of disturbed differentiation orexcess proliferation of the epidermis or mucous membrane, andcardiovascular disorders.

The compositions contain one or more compounds provided herein. Thecompounds are preferably formulated into suitable pharmaceuticalpreparations such as solutions, suspensions, tablets, dispersibletablets, pills, capsules, powders, sustained release formulations orelixirs, for oral administration or in sterile solutions or suspensionsfor parenteral administration, as well as transdermal patch preparationand dry powder inhalers. Typically the compounds described above areformulated into pharmaceutical compositions using techniques andprocedures well known in the art (see, e.g., Ansel Introduction toPharmaceutical Dosage Forms, Fourth Edition 1985, 126).

In the compositions, effective concentrations of one or more compoundsor pharmaceutically acceptable derivatives is (are) mixed with asuitable pharmaceutical carrier or vehicle. The compounds may bederivatized as the corresponding salts, esters, enol ethers or esters,acids, bases, solvates, hydrates or prodrugs prior to formulation, asdescribed above. The concentrations of the compounds in the compositionsare effective for delivery of an amount, upon administration, thattreats, prevents, or ameliorates one or more of the symptoms of diseasesor disorders associated with nuclear receptor activity or in whichnuclear receptor activity is implicated. Such diseases or disordersinclude, but are not limited to, hypercholesterolemia,hyperlipoproteinemia, hypertriglyceridemia, lipodystrophy,hyperglycemia, diabetes mellitus, dyslipidemia, atherosclerosis,gallstone disease, acne vulgaris, acneiform skin conditions, diabetes,Parkinson's disease, cancer, Alzheimer's disease, inflammation,immunological disorders, lipid disorders, obesity, conditionscharacterized by a perturbed epidermal barrier function, hyperlipidemia,cholestasis, peripheral occlusive disease, ischemic stroke, conditionsof disturbed differentiation or excess proliferation of the epidermis ormucous membrane, and cardiovascular disorders.

Typically, the compositions are formulated for single dosageadministration. To formulate a composition, the weight fraction ofcompound is dissolved, suspended, dispersed or otherwise mixed in aselected vehicle at an effective concentration such that the treatedcondition is relieved or ameliorated. Pharmaceutical carriers orvehicles suitable for administration of the compounds provided hereininclude any such carriers known to those skilled in the art to besuitable for the particular mode of administration.

In addition, the compounds may be formulated as the solepharmaceutically active ingredient in the composition or may be combinedwith other active ingredients. Liposomal suspensions, includingtissue-targeted liposomes, such as tumor-targeted liposomes, may also besuitable as pharmaceutically acceptable carriers. These may be preparedaccording to methods known to those skilled in the art. For example,liposome formulations may be prepared as described in U.S. Pat. No.4,522,811. Briefly, liposomes such as multilamellar vesicles (MLVs) maybe formed by drying down egg phosphatidyl choline and brain phosphatidylserine (7:3 molar ratio) on the inside of a flask. A solution of acompound provided herein in phosphate buffered saline lacking divalentcations (PBS) is added and the flask shaken until the lipid film isdispersed. The resulting vesicles are washed to remove unencapsulatedcompound, pelleted by centrifugation, and then resuspended in PBS.

The active compound is included in the pharmaceutically acceptablecarrier in an amount sufficient to exert a therapeutically useful effectin the absence of undesirable side effects on the patient treated. Thetherapeutically effective concentration may be determined empirically bytesting the compounds in in vitro and in vivo systems described hereinand in International Patent Application Publication Nos. 99/27365 and00/25134 (see, e.g., EXAMPLES 15 and 16) and then extrapolated therefromfor dosages for humans.

The concentration of active compound in the pharmaceutical compositionwill depend on absorption, inactivation and excretion rates of theactive compound, the physicochemical characteristics of the compound,the dosage schedule, and amount administered as well as other factorsknown to those of skill in the art. For example, the amount that isdelivered is sufficient to ameliorate one or more of the symptoms ofdiseases or disorders associated with nuclear receptor activity or inwhich nuclear receptor activity is implicated, as described herein.

Typically a therapeutically effective dosage should produce a serumconcentration of active ingredient of from about 0.1 ng/ml to about50-100 μg/ml. The pharmaceutical compositions typically should provide adosage of from about 0.001 mg to about 2000 mg of compound per kilogramof body weight per day. Pharmaceutical dosage unit forms are prepared toprovide from about 1 mg to about 1000 mg and preferably from about 10 toabout 500 mg of the essential active ingredient or a combination ofessential ingredients per dosage unit form.

The active ingredient may be administered at once, or may be dividedinto a number of smaller doses to be administered at intervals of time.It is understood that the precise dosage and duration of treatment is afunction of the disease being treated and may be determined empiricallyusing known testing protocols or by extrapolation from in vivo or invitro test data. It is to be noted that concentrations and dosage valuesmay also vary with the severity of the condition to be alleviated. It isto be further understood that for any particular subject, specificdosage regimens should be adjusted over time according to the individualneed and the professional judgment of the person administering orsupervising the administration of the compositions, and that theconcentration ranges set forth herein are exemplary only and are notintended to limit the scope or practice of the claimed compositions.

Pharmaceutically acceptable derivatives include acids, bases, enolethers and esters, salts, esters, hydrates, solvates and prodrug forms.The derivative is selected such that its pharmacokinetic properties aresuperior to the corresponding neutral compound.

Thus, effective concentrations or amounts of one or more of thecompounds described herein or pharmaceutically acceptable derivativesthereof are mixed with a suitable pharmaceutical carrier or vehicle forsystemic, topical or local administration to form pharmaceuticalcompositions. Compounds are included in an amount effective forameliorating one or more symptoms of, or for treating or preventingdiseases or disorders associated with nuclear receptor activity or inwhich nuclear receptor activity is implicated, as described herein. Theconcentration of active compound in the composition will depend onabsorption, inactivation, excretion rates of the active compound, thedosage schedule, amount administered, particular formulation as well asother factors known to those of skill in the art.

The compositions are intended to be administered by a suitable route,including orally, parenterally, rectally, topically and locally. Fororal administration, capsules and tablets are presently preferred. Thecompositions are in liquid, semi-liquid or solid form and are formulatedin a manner suitable for each route of administration. Preferred modesof administration include parenteral and oral modes of administration.Oral administration is presently most preferred.

Solutions or suspensions used for parenteral, intradermal, subcutaneous,or topical application can include any of the following components: asterile diluent, such as water for injection, saline solution, fixedoil, polyethylene glycol, glycerine, propylene glycol or other syntheticsolvent; antimicrobial agents, such as benzyl alcohol and methylparabens; antioxidants, such as ascorbic acid and sodium bisulfite;chelating agents, such as ethylenediaminetetraacetic acid (EDTA);buffers, such as acetates, citrates and phosphates; and agents for theadjustment of tonicity such as sodium chloride or dextrose. Parenteralpreparations can be enclosed in ampules, disposable syringes or singleor multiple dose vials made of glass, plastic or other suitablematerial.

In instances in which the compounds exhibit insufficient solubility,methods for solubilizing compounds may be used. Such methods are knownto those of skill in this art, and include, but are not limited to,using cosolvents, such as dimethylsulfoxide (DMSO), using surfactants,such as TWEEN®, or dissolution in aqueous sodium bicarbonate.Derivatives of the compounds, such as prodrugs of the compounds may alsobe used in formulating effective pharmaceutical compositions.

Upon mixing or addition of the compound(s), the resulting mixture may bea solution, suspension, emulsion or the like. The form of the resultingmixture depends upon a number of factors, including the intended mode ofadministration and the solubility of the compound in the selectedcarrier or vehicle. The effective concentration is sufficient forameliorating the symptoms of the disease, disorder or condition treatedand may be empirically determined.

The pharmaceutical compositions are provided for administration tohumans and animals in unit dosage forms, such as tablets, capsules,pills, powders, granules, sterile parenteral solutions or suspensions,and oral solutions or suspensions, and oil-water emulsions containingsuitable quantities of the compounds or pharmaceutically acceptablederivatives thereof. The pharmaceutically therapeutically activecompounds and derivatives thereof are typically formulated andadministered in unit-dosage forms or multiple-dosage forms. Unit-doseforms as used herein refers to physically discrete units suitable forhuman and animal subjects and packaged individually as is known in theart. Each unit-dose contains a predetermined quantity of thetherapeutically active compound sufficient to produce the desiredtherapeutic effect, in association with the required pharmaceuticalcarrier, vehicle or diluent. Examples of unit-dose forms includeampoules and syringes and individually packaged tablets or capsules.Unit-dose forms may be administered in fractions or multiples thereof. Amultiple-dose form is a plurality of identical unit-dosage formspackaged in a single container to be administered in segregatedunit-dose form. Examples of multiple-dose forms include vials, bottlesof tablets or capsules or bottles of pints or gallons. Hence, multipledose form is a multiple of unit-doses which are not segregated inpackaging.

The composition can contain along with the active ingredient: a diluentsuch as lactose, sucrose, dicalcium phosphate, orcarboxymethylcellulose; a lubricant, such as magnesium stearate, calciumstearate and talc; and a binder such as starch, natural gums, such asgum acacia gelatin, glucose, molasses, polyinylpyrrolidine, cellulosesand derivatives thereof, povidone, crospovidones and other such bindersknown to those of skill in the art. Liquid pharmaceuticallyadministrable compositions can, for example, be prepared by dissolving,dispersing, or otherwise mixing an active compound as defined above andoptional pharmaceutical adjuvants in a carrier, such as, for example,water, saline, aqueous dextrose, glycerol, glycols, ethanol, and thelike, to thereby form a solution or suspension. If desired, thepharmaceutical composition to be administered may also contain minoramounts of nontoxic auxiliary substances such as wetting agents,emulsifying agents, or solubilizing agents, pH buffering agents and thelike, for example, acetate, sodium citrate, cyclodextrine derivatives,sorbitan monolaurate, triethanolamine sodium acetate, triethanolamineoleate, and other such agents. Actual methods of preparing such dosageforms are known, or will be apparent, to those skilled in this art; forexample, see Remington's Pharmaceutical Sciences, Mack PublishingCompany, Easton, Pa., 15th Edition, 1975. The composition or formulationto be administered will, in any event, contain a quantity of the activecompound in an amount sufficient to alleviate the symptoms of thetreated subject.

Dosage forms or compositions containing active ingredient in the rangeof 0.005% to 100% with the balance made up from non-toxic carrier may beprepared. For oral administration, a pharmaceutically acceptablenon-toxic composition is formed by the incorporation of any of thenormally employed excipients, such as, for example pharmaceutical gradesof mannitol, lactose, starch, magnesium stearate, talcum, cellulosederivatives, sodium crosscarmellose, glucose, sucrose, magnesiumcarbonate or sodium saccharin. Such compositions include solutions,suspensions, tablets, capsules, powders and sustained releaseformulations, such as, but not limited to, implants andmicroencapsulated delivery systems, and biodegradable, biocompatiblepolymers, such as collagen, ethylene vinyl acetate, polyanhydrides,polyglycolic acid, polyorthoesters, polylactic acid and others. Methodsfor preparation of these compositions are known to those skilled in theart. The contemplated compositions may contain 0.001%-100% activeingredient, preferably 0.1-85%, typically 75-95%.

The active compounds or pharmaceutically acceptable derivatives may beprepared with carriers that protect the compound against rapidelimination from the body, such as time release formulations orcoatings. The compositions may include other active compounds to obtaindesired combinations of properties. The compounds provided herein, orpharmaceutically acceptable derivatives thereof as described herein, mayalso be advantageously administered for therapeutic or prophylacticpurposes together with another pharmacological agent known in thegeneral art to be of value in treating one or more of the diseases ormedical conditions referred to hereinabove, such as diseases ordisorders associated with nuclear receptor activity or in which nuclearreceptor activity is implicated. It is to be understood that suchcombination therapy constitutes a further aspect of the compositions andmethods of treatment provided herein.

1. Compositions for Oral Administration

Oral pharmaceutical dosage forms are either solid, gel or liquid. Thesolid dosage forms are tablets, capsules, granules, and bulk powders.Types of oral tablets include compressed, chewable lozenges and tabletswhich may be enteric-coated, sugar-coated or film-coated. Capsules maybe hard or soft gelatin capsules, while granules and powders may beprovided in non-effervescent or effervescent form with the combinationof other ingredients known to those skilled in the art.

In certain embodiments, the formulations are solid dosage forms,preferably capsules or tablets. The tablets, pills, capsules, trochesand the like can contain any of the following ingredients, or compoundsof a similar nature: a binder; a diluent; a disintegrating agent; alubricant; a glidant; a sweetening agent; and a flavoring agent.

Examples of binders include microcrystalline cellulose, gum tragacanth,glucose solution, acacia mucilage, gelatin solution, sucrose and starchpaste. Lubricants include talc, starch, magnesium or calcium stearate,lycopodium and stearic acid. Diluents include, for example, lactose,sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate.Glidants include, but are not limited to, colloidal silicon dioxide.Disintegrating agents include crosscarmellose sodium, sodium starchglycolate, alginic acid, corn starch, potato starch, bentonite,methylcellulose, agar and carboxymethylcellulose. Coloring agentsinclude, for example, any of the approved certified water soluble FD andC dyes, mixtures thereof; and water insoluble FD and C dyes suspended onalumina hydrate. Sweetening agents include sucrose, lactose, mannitoland artificial sweetening agents such as saccharin, and any number ofspray dried flavors. Flavoring agents include natural flavors extractedfrom plants such as fruits and synthetic blends of compounds whichproduce a pleasant sensation, such as, but not limited to peppermint andmethyl salicylate. Wetting agents include propylene glycol monostearate,sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylenelaural ether. Emetic-coatings include fatty acids, fats, waxes, shellac,ammoniated shellac and cellulose acetate phthalates. Film coatingsinclude hydroxyethylcellulose, sodium carboxymethylcellulose,polyethylene glycol 4000 and cellulose acetate phthalate.

If oral administration is desired, the compound could be provided in acomposition that protects it from the acidic environment of the stomach.For example, the composition can be formulated in an enteric coatingthat maintains its integrity in the stomach and releases the activecompound in the intestine. The composition may also be formulated incombination with an antacid or other such ingredient.

When the dosage unit form is a capsule, it can contain, in addition tomaterial of the above type, a liquid carrier such as a fatty oil. Inaddition, dosage unit forms can contain various other materials whichmodify the physical form of the dosage unit, for example, coatings ofsugar and other enteric agents. The compounds can also be administeredas a component of an elixir, suspension, syrup, wafer, sprinkle, chewinggum or the like. A syrup may contain, in addition to the activecompounds, sucrose as a sweetening agent and certain preservatives, dyesand colorings and flavors.

The active materials can also be mixed with other active materials whichdo not impair the desired action, or with materials that supplement thedesired action, such as antacids, H2 blockers, and diuretics. The activeingredient is a compound or pharmaceutically acceptable derivativethereof as described herein. Higher concentrations, up to about 98% byweight of the active ingredient may be included.

Pharmaceutically acceptable carriers included in tablets are binders,lubricants, diluents, disintegrating agents, coloring agents, flavoringagents, and wetting agents. Enteric-coated tablets, because of theenteric-coating, resist the action of stomach acid and dissolve ordisintegrate in the neutral or alkaline intestines. Sugar-coated tabletsare compressed tablets to which different layers of pharmaceuticallyacceptable substances are applied. Film-coated tablets are compressedtablets which have been coated with a polymer or other suitable coating.

Multiple compressed tablets are compressed tablets made by more than onecompression cycle utilizing the pharmaceutically acceptable substancespreviously mentioned. Coloring agents may also be used in the abovedosage forms. Flavoring and sweetening agents are used in compressedtablets, sugar-coated, multiple compressed and chewable tablets.Flavoring and sweetening agents are especially useful in the formationof chewable tablets and lozenges.

Liquid oral dosage forms include aqueous solutions, emulsions,suspensions, solutions and/or suspensions reconstituted fromnon-effervescent granules and effervescent preparations reconstitutedfrom effervescent granules. Aqueous solutions include, for example,elixirs and syrups. Emulsions are either oil-in-water or water-in-oil.

Elixirs are clear, sweetened, hydroalcoholic preparations.Pharmaceutically acceptable carriers used in elixirs include solvents.Syrups are concentrated aqueous solutions of a sugar, for example,sucrose, and may contain a preservative. An emulsion is a two-phasesystem in which one liquid is dispersed in the form of small globulesthroughout another liquid. Pharmaceutically acceptable carriers used inemulsions are non-aqueous liquids, emulsifying agents and preservatives.Suspensions use pharmaceutically acceptable suspending agents andpreservatives. Pharmaceutically acceptable substances used innon-effervescent granules, to be reconstituted into a liquid oral dosageform, include diluents, sweeteners and wetting agents. Pharmaceuticallyacceptable substances used in effervescent granules, to be reconstitutedinto a liquid oral dosage form, include organic acids and a source ofcarbon dioxide. Coloring and flavoring agents are used in all of theabove dosage forms.

Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examplesof preservatives include glycerin, methyl and propylparaben, benzoicadd, sodium benzoate and alcohol. Examples of non-aqueous liquidsutilized in emulsions include mineral oil and cottonseed oil. Examplesof emulsifying agents include gelatin, acacia, tragacanth, bentonite,and surfactants such as polyoxyethylene sorbitan monooleate. Suspendingagents include sodium carboxymethylcellulose, pectin, tragacanth, Veegumand acacia. Diluents include lactose and sucrose. Sweetening agentsinclude sucrose, syrups, glycerin and artificial sweetening agents suchas saccharin. Wetting agents include propylene glycol monostearate,sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylenelauryl ether. Organic adds include citric and tartaric acid. Sources ofcarbon dioxide include sodium bicarbonate and sodium carbonate. Coloringagents include any of the approved certified water soluble FD and Cdyes, and mixtures thereof. Flavoring agents include natural flavorsextracted from plants such fruits, and synthetic blends of compoundswhich produce a pleasant taste sensation.

For a solid dosage form, the solution or suspension, in for examplepropylene carbonate, vegetable oils or triglycerides, is preferablyencapsulated in a gelatin capsule. Such solutions, and the preparationand encapsulation thereof, are disclosed in U.S. Pat. Nos. 4,328,245;4,409,239; and 4,410,545. For a liquid dosage form, the solution, e.g.,for example, in a polyethylene glycol, may be diluted with a sufficientquantity of a pharmaceutically acceptable liquid carrier, e.g., water,to be easily measured for administration.

Alternatively, liquid or semi-solid oral formulations may be prepared bydissolving or dispersing the active compound or salt in vegetable oils,glycols, triglycerides, propylene glycol esters (e.g., propylenecarbonate) and other such carriers, and encapsulating these solutions orsuspensions in hard or soft gelatin capsule shells. Other usefulformulations include those set forth in U.S. Pat. Nos. Re 28,819 and4,358,603. Briefly, such formulations include, but are not limited to,those containing a compound provided herein, a dialkylated mono- orpoly-alkylene glycol, including, but not limited to,1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethyleneglycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether,polyethylene glycol-750-dimethyl ether wherein 350, 550 and 750 refer tothe approximate average molecular weight of the polyethylene glycol, andone or more antioxidants, such as butylated hydroxytoluene (BHT),butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone,hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malicacid, sorbitol, phosphoric acid, thiodipropionic acid and its esters,and dithiocarbamates.

Other formulations include, but are not limited to, aqueous alcoholicsolutions including a pharmaceutically acceptable acetal. Alcohols usedin these formulations are any pharmaceutically acceptable water-misciblesolvents having one or more hydroxyl groups, including, but not limitedto, propylene glycol and ethanol. Acetals include, but are not limitedto, di(lower alkyl)acetals of lower alkyl aldehydes such as acetaldehydediethyl acetal.

In all embodiments, tablets and capsules formulations may be coated asknown by those of skill in the art in order to modify or sustaindissolution of the active ingredient. Thus, for example, they may becoated with a conventional enterically digestible coating, such asphenylsalicylate, waxes and cellulose acetate phthalate.

2. Injectables, Solutions and Emulsions

Parenteral administration, generally characterized by injection, eithersubcutaneously, intramuscularly or intravenously is also contemplatedherein. Injectables can be prepared in conventional forms, either asliquid solutions or suspensions, solid forms suitable for solution orsuspension in liquid prior to injection, or as emulsions. Suitableexcipients are, for example, water, saline, dextrose, glycerol orethanol. In addition, if desired, the pharmaceutical compositions to beadministered may also contain minor amounts of non-toxic auxiliarysubstances such as wetting or emulsifying agents, pH buffering agents,stabilizers, solubility enhancers, and other such agents, such as forexample, sodium acetate, sorbitan monolaurate, triethanolamine oleateand cyclodextrins. Implantation of a slow-release or sustained-releasesystem, such that a constant level of dosage is maintained (see, e.g.,U.S. Pat. No. 3,710,795) is also contemplated herein. Briefly, acompound provided herein is dispersed in a solid inner matrix, e.g.,polymethylmethacrylate, polybutylmethacrylate, plasticized orunplasticized polyvinylchloride, plasticized nylon, plasticizedpolyethyleneterephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetatecopolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonatecopolymers, hydrophilic polymers such as hydrogels of esters of acrylicand methacrylic acid, collagen, cross-linked polyvinylalcohol andcross-linked partially hydrolyzed polyvinyl acetate, that is surroundedby an outer polymeric membrane, e.g., polyethylene, polypropylene,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,ethylenevinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride,vinylchloride copolymers with vinyl acetate, vinylidene chloride,ethylene and propylene, ionomer polyethylene terephthalate, butyl rubberepichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer, that is insoluble in body fluids.The compound diffuses through the outer polymeric membrane in a releaserate controlling step. The percentage of active compound contained insuch parenteral compositions is highly dependent on the specific naturethereof, as well as the activity of the compound and the needs of thesubject.

Parenteral administration of the compositions includes intravenous,subcutaneous and intramuscular administrations. Preparations forparenteral administration include sterile solutions ready for injection,sterile dry soluble products, such as lyophilized powders, ready to becombined with a solvent just prior to use, including hypodermic tablets,sterile suspensions ready for injection, sterile dry insoluble productsready to be combined with a vehicle just prior to use and sterileemulsions. The solutions may be either aqueous or nonaqueous.

If administered intravenously, suitable carriers include physiologicalsaline or phosphate buffered saline (PBS), and solutions containingthickening and solubilizing agents, such as glucose, polyethyleneglycol, and polypropylene glycol and mixtures thereof.

Pharmaceutically acceptable carriers used in parenteral preparationsinclude aqueous vehicles, nonaqueous vehicles, antimicrobial agents,isotonic agents, buffers, antioxidants, local anesthetics, suspendingand dispersing agents, emulsifying agents, sequestering or chelatingagents and other pharmaceutically-acceptable substances.

Examples of aqueous vehicles include Sodium Chloride Injection, RingersInjection, Isotonic Dextrose Injection, Sterile Water Injection,Dextrose and Lactated Ringers Injection. Nonaqueous parenteral vehiclesinclude fixed oils of vegetable origin, cottonseed oil, corn oil, sesameoil and peanut oil. Antimicrobial agents in bacteriostatic orfungistatic concentrations must be added to parenteral preparationspackaged in multiple-dose containers which include phenols or cresols,mercurials, benzyl alcohol, chlorobutanol, methyl and propylp-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride andbenzethonium chloride. Isotonic agents include sodium chloride anddextrose. Buffers include phosphate and citrate. Antioxidants includesodium bisulfate. Local anesthetics include procaine hydrochloride.Suspending and dispersing agents include sodium carboxymethylcelluose,hydroxypropyl methylcellulose and polyvinylpyrrolidone. Emulsifyingagents include Polysorbate 80 (TWEEN® 80). A sequestering or chelatingagent of metal ions include EDTA. Pharmaceutical carriers also includeethyl alcohol, polyethylene glycol and propylene glycol for watermiscible vehicles and sodium hydroxide, hydrochloric acid, citric add orlactic acid for pH adjustment.

The concentration of the pharmaceutically active compound is adjusted sothat an injection provides an effective amount to produce the desiredpharmacological effect. The exact dose depends on the age, weight andcondition of the patient or animal as is known in the art.

The unit-dose parenteral preparations are packaged in an ampoule, a vialor a syringe with a needle. All preparations for parenteraladministration must be sterile, as is known and practiced in the art.

Illustratively, intravenous or intraarterial infusion of a sterileaqueous solution containing an active compound is an effective mode ofadministration. Another embodiment is a sterile aqueous or oily solutionor suspension containing an active material injected as necessary toproduce the desired pharmacological effect.

Injectables are designed for local and systemic administration.Typically a therapeutically effective dosage is formulated to contain aconcentration of at least about 0.1% w/w up to about 90% w/w or more,preferably more than 1% w/w of the active compound to the treatedtissue(s). The active ingredient may be administered at once, or may bedivided into a number of smaller doses to be administered at intervalsof time. It is understood that the precise dosage and duration oftreatment is a function of the tissue being treated and may bedetermined empirically using known testing protocols or by extrapolationfrom in vivo or in vitro test data. It is to be noted thatconcentrations and dosage values may also vary with the age of theindividual treated. It is to be further understood that for anyparticular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of theformulations, and that the concentration ranges set forth herein areexemplary only and are not intended to limit the scope or practice ofthe claimed formulations.

The compound may be suspended in micronized or other suitable form ormay be derivatized to produce a more soluble active product or toproduce a prodrug. The form of the resulting mixture depends upon anumber of factors, including the intended mode of administration and thesolubility of the compound in the selected carrier or vehicle. Theeffective concentration is sufficient for ameliorating the symptoms ofthe condition and may be empirically determined.

3. Lyophilized Powders

Of interest herein are also lyophilized powders, which can bereconstituted for administration as solutions, emulsions and othermixtures. They may also be reconstituted and formulated as solids orgels.

The sterile, lyophilized powder is prepared by dissolving a compoundprovided herein, or a pharmaceutically acceptable derivative thereof, ina suitable solvent. The solvent may contain an excipient which improvesthe stability or other pharmacological component of the powder orreconstituted solution, prepared from the powder. Excipients that may beused include, but are not limited to, dextrose, sorbital, fructose, cornsyrup, xylitol, glycerin, glucose, sucrose or other suitable agent. Thesolvent may also contain a buffer, such as citrate, sodium or potassiumphosphate or other such buffer known to those of skill in the art at,typically, about neutral pH. Subsequent sterile filtration of thesolution followed by lyophilization under standard conditions known tothose of skill in the art provides the desired formulation. Generally,the resulting solution will be apportioned into vials forlyophilization. Each vial will contain a single dosage (10-1000 mg,preferably 100-500 mg) or multiple dosages of the compound. Thelyophilized powder can be stored under appropriate conditions, such asat about 4° C. to room temperature.

Reconstitution of this lyophilized powder with water for injectionprovides a formulation for use in parenteral administration. Forreconstitution, about 1-50 mg, preferably 5-35 mg, more preferably about9-30 mg of lyophilized powder, is added per mL of sterile water or othersuitable carrier. The precise amount depends upon the selected compound.Such amount can be empirically determined.

4. Topical Administration

Topical mixtures are prepared as described for the local and systemicadministration. The resulting mixture may be a solution, suspension,emulsions or the like and are formulated as creams, gels, ointments,emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes,foams, aerosols, irrigations, sprays, suppositories, bandages, dermalpatches or any other formulations suitable for topical administration.

The compounds or pharmaceutically acceptable derivatives thereof may beformulated as aerosols for topical application, such as by inhalation(see, e.g., U.S. Pat. Nos. 4,044,126, 4,414,209, and 4,364,923, whichdescribe aerosols for delivery of a steroid useful for treatment ofinflammatory diseases, particularly asthma). These formulations foradministration to the respiratory tract can be in the form of an aerosolor solution for a nebulizer, or as a microfine powder for insufflation,alone or in combination with an inert carrier such as lactose. In such acase, the particles of the formulation will typically have diameters ofless than 50 microns, preferably less than 10 microns.

The compounds may be formulated for local or topical application, suchas for topical application to the skin and mucous membranes, such as inthe eye, in the form of gels, creams, and lotions and for application tothe eye or for intracisternal or intraspinal application. Topicaladministration is contemplated for transdermal delivery and also foradministration to the eyes or mucosa, or for inhalation therapies. Nasalsolutions of the active compound alone or in combination with otherpharmaceutically acceptable excipients can also be administered.

These solutions, particularly those intended for ophthalmic use, may beformulated as 0.01%-10% isotonic solutions, pH about 5-7, withappropriate salts.

5. Compositions for Other Routes of Administration

Other routes of administration, such as topical application, transdermalpatches, and rectal administration are also contemplated herein.

For example, pharmaceutical dosage forms for rectal administration arerectal suppositories, capsules and tablets for systemic effect. Rectalsuppositories are used herein mean solid bodies for insertion into therectum which melt or soften at body temperature releasing one or morepharmacologically or therapeutically active ingredients.Pharmaceutically acceptable substances utilized in rectal suppositoriesare bases or vehicles and agents to raise the melting point. Examples ofbases include cocoa butter (theobroma oil), glycerin-gelatin, carbowax(polyoxyethylene glycol) and appropriate mixtures of mono-, di- andtriglycerides of fatty adds. Combinations of the various bases may beused. Agents to raise the melting point of suppositories includespermaceti and wax. Rectal suppositories may be prepared either by thecompressed method or by molding. The typical weight of a rectalsuppository is about 2 to 3 gm.

Tablets and capsules for rectal administration are manufactured usingthe same pharmaceutically acceptable substance and by the same methodsas for formulations for oral administration.

6. Articles of Manufacture

The compounds or pharmaceutically acceptable derivatives may be packagedas articles of manufacture containing packaging material, a compound orpharmaceutically acceptable derivative thereof provided herein, which iseffective for modulating the activity of nuclear receptors, includingFXR and/or orphan nuclear receptors, or for treatment, prevention oramelioration of one or more symptoms of nuclear receptor, including FXRand/or orphan nuclear receptor, mediated diseases or disorders, ordiseases or disorders in which nuclear receptor activity, including FXRand/or orphan nuclear receptor activity, is implicated, within thepackaging material, and a label that indicates that the compound orcomposition, or pharmaceutically acceptable derivative thereof, is usedfor modulating the activity of nuclear receptors, including FXR and/ororphan nuclear receptors, or for treatment, prevention or ameliorationof one or more symptoms of nuclear receptor, including FXR and/or orphannuclear receptor, mediated diseases or disorders, or diseases ordisorders in which nuclear receptor activity, including FXR and/ororphan nuclear receptor activity, is implicated.

The articles of manufacture provided herein contain packaging materials.Packaging materials for use in packaging pharmaceutical products arewell known to those of skill in the art. See, e.g., U.S. Pat. Nos.5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packagingmaterials include, but are not limited to, blister packs, bottles,tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, andany packaging material suitable for a selected formulation and intendedmode of administration and treatment. A wide array of formulations ofthe compounds and compositions provided herein are contemplated as are avariety of treatments for any disease or disorder in which nuclearreceptor activity, including FXR and/or orphan nuclear receptoractivity, is implicated as a mediator or contributor to the symptoms orcause.

E. Evaluation of the Activity of the Compounds

Standard physiological, pharmacological and biochemical procedures areavailable for testing the compounds to identify those that possessbiological activities that modulate the activity or nuclear receptors,including FXR and/or orphan nuclear receptors. Such assays include, forexample, biochemical assays such as binding assays, fluorescencepolarization assays, FRET based coactivator recruitment assays (seegenerally Glickman et al., J. Biomolecular Screening (2002), Vol. 7, No.1, pp. 3-10), as well as cell based assays including the co-transfectionassay, the use of LBD-Gal 4 chimeras and protein-protein interactionassays (see, Lehmann, et al., J. Biol. Chem. (1997), Vol. 272, No. 6,pp. 3137-3140 (1997).

High throughput screening systems are commercially available (see, e.g.,Zymark Corp., Hopkinton, Mass.; Air Technical Industries, Mentor, Ohio;Beckman Instruments Inc., Fullerton, Calif.; Precision Systems, Inc.,Natick, Mass.) that enable these assays to be run in a high throughputmode. These systems typically automate entire procedures, including allsample and reagent pipetting, liquid dispensing timed incubations, andfinal readings of the microplate in detector(s) appropriate for theassay. These configurable systems provide high throughput and rapidstart up as well as a high degree of flexibility and customization. Themanufacturers of such systems provide detailed protocols for varioushigh throughput systems. Thus, for example, Zymark Corp. providestechnical bulletins describing screening systems for detecting themodulation of gene transcription, ligand binding, and the like.

Assays that do not require washing or liquid separation steps arepreferred for such high throughput screening systems and includebiochemical assays such as fluorescence polarization assays (see forexample, Owicki, J., Biomol. Screen (2000), October, Vol. 5, No. 5, p.297) scintillation proximity assays (SPA) (see, for example, Carpenteret al., Methods Mol. Biol. (2002), Vol. 190, pp. 31-49) and fluorescenceresonance energy transfer energy transfer (FRET) or time resolved FRETbased coactivator recruitment assays (Mukherjee et al., J. SteroidBiochem. Mol. Biol. (2002), Vol. 81, No. 3, pp. 217-25; Zhou et al.,Mol. Endocrinol. (1998), Vol. 12, No. 10, pp. 1594-604). Generally suchassays can be preformed using either the full length receptor, orisolated ligand binding domain (LBD). In the case of FXR, the LBDcomprises amino acids 244 to 472 of the full length sequence.

If a fluorescently labeled ligand is available, fluorescencepolarization assays provide a way of detecting binding of compounds tothe nuclear receptor of interest by measuring changes in fluorescencepolarization that occur as a result of the displacement of a traceamount of the label ligand by the compound. Additionally this approachcan also be used to monitor the ligand dependent association of afluorescently labeled coactivator peptide to the nuclear receptor ofinterest to detect ligand binding to the nuclear receptor of interest.

The ability of a compound to bind to a receptor, or heterodimer complexwith RXR, can also be measured in a homogeneous assay format byassessing the degree to which the compound can compete off aradiolabelled ligand with known affinity for the receptor using ascintillation proximity assay (SPA). In this approach, the radioactivityemitted by a radiolabelled compound generates an optical signal when itis brought into close proximity to a scintillant such as a Ysi-coppercontaining bead, to which the nuclear receptor is bound. If theradiolabelled compound is displaced from the nuclear receptor the amountof light emitted from the nuclear receptor bound scintillant decreases,and this can be readily detected using standard microplate liquidscintillation plate readers such as, for example, a Wallac MicroBetareader.

The heterodimerization of FXR with RXRα can also be measured byfluorescence resonance energy transfer (FRET), or time resolved FRET, tomonitor the ability of the compounds provided herein to bind to FXR orother nuclear receptors. Both approaches rely upon the fact that energytransfer from a donor molecule to an acceptor molecule only occurs whendonor and acceptor are in close proximity. Typically the purified LBD ofthe nuclear receptor of interest is labeled with biotin then mixed withstoichiometric amounts of europium labeled streptavidin (Wallac Inc.),and the purified LBD of RXRα is labeled with a suitable fluorophore suchas CY5™. Equimolar amounts of each modified LBD are mixed together andallowed to equilibrate for at least 1 hour prior to addition to eithervariable or constant concentrations of the sample for which the affinityis to be determined. After equilibration, the time-resolved fluorescentsignal is quantitated using a fluorescent plate reader. The affinity ofthe compound can then be estimated from a plot of fluorescence versusconcentration of compound added.

This approach can also be exploited to measure the ligand dependentinteraction of a co-activator peptide with a nuclear receptor in orderto characterize the agonist or antagonist activity of the compoundsdisclosed herein. Typically the assay in this case involves the use arecombinant Glutathione-S-transferase (GST)-nuclear receptor ligandbinding domain (LBD) fusion protein and a synthetic biotinylated peptidesequenced derived from the receptor interacting domain of a co-activatorpeptide such as the steroid receptor coactivator 1 (SRC-1). TypicallyGST-LBD is labeled with a europium chelate (donor) via a europium-taggedanti-GST antibody, and the coactivator peptide is labeled withallophycocyanin via a streptavidin-biotin linkage.

In the presence of an agonist for the nuclear receptor, the peptide isrecruited to the GST-LBD bringing europium and allophycocyanin into doseproximity to enable energy transfer from the europium chelate to theallophycocyanin. Upon excitation of the complex with light at 340 nmexcitation energy absorbed by the europium chelate is transmitted to theallophycocyanin moiety resulting in emission at 665 nm. If the europiumchelate is not brought in to close proximity to the allophycocyaninmoiety there is little or no energy transfer and excitation of theeuropium chelate results in emission at 615 nm. Thus the intensity oflight emitted at 665 nm gives an indication of the strength of theprotein-protein interaction. The activity of a nuclear receptorantagonist can be measured by determining the ability of a compound tocompetitively inhibit (i.e., IC₅₀) the activity of an agonist for thenuclear receptor.

In addition a variety of cell based assay methodologies may besuccessfully used in screening assays to identify and profile thespecificity of compounds of the present invention. These approachesinclude the co-transfection assay, translocation assays, complementationassays and the use of gene activation technologies to over expressendogenous nuclear receptors.

Three basic variants of the co-transfection assay strategy exist,co-transfection assays using full-length nuclear receptor, cotransfection assays using chimeric nuclear receptors comprising theligand binding domain of the nuclear receptor of interest fused to aheterologous DNA binding domain, and assays based around the use of themammalian two hybrid assay system.

The basic co-transfection assay is based on the co-transfection into thecell of an expression plasmid to express the nuclear receptor ofinterest in the cell with a reporter plasmid comprising a reporter genewhose expression is under the control of DNA sequence that is capable ofinteracting with that nuclear receptor. (See, for example, U.S. Pat.Nos. 5,071,773; 5,298,429, 6,416,957, WO 00/76523). Treatment of thetransfected cells with an agonist for the nuclear receptor increases thetranscriptional activity of that receptor which is reflected by anincrease in expression of the reporter gene, which may be measured by avariety of standard procedures.

For those receptors that function as heterodimers with RXR, such as FXR,the co-transfection assay typically includes the use of expressionplasmids for both the nuclear receptor of interest and RXR. Typicalco-transfection assays require access to the full length nuclearreceptor and suitable response elements that provide sufficientscreening sensitivity and specificity to the nuclear receptor ofinterest.

Genes encoding the following full-length previously described proteins,which are suitable for use in the co-transfection studies and profilingthe compounds described herein, include rat FXR (GenBank Accession No.NM_(—)021745), human FXR (GenBank Accession No. NM_(—)005123), human RXRα (GenBank Accession No. NM_(—)002957), human RXR β (GenBank AccessionNo. XM_(—)042579), human RXR.γ (GenBank Accession No. XM_(—)053680),human LXR α (GenBank Accession No. NM_(—)005693), human LXR β (GenBankAccession No. NM 007121), human PPARα (GenBank Accession No. NM₁₃005036) and human PPAR δ (GenBank Accession No. NM_(—)006238).

Reporter plasmids may be constructed using standard molecular biologicaltechniques by placing cDNA encoding for the reporter gene downstreamfrom a suitable minimal promoter. For example luciferase reporterplasmids may be constructed by placing cDNA encoding firefly luciferaseimmediately down stream from the herpes virus thymidine kinase promoter(located at nucleotides residues-105 to +51 of the thymidine kinasenucleotide sequence) which is linked in turn to the various responseelements.

Numerous methods of co-transfecting the expression and reporter plasmidsare known to those of skill in the art and may be used for theco-transfection assay to introduce the plasmids into a suitable celltype. Typically such a cell will not endogenously express nuclearreceptors that interact with the response elements used in the reporterplasmid.

Numerous reporter gene systems are known in the art and include, forexample, alkaline phosphatase Berger, J., et al. (1988) Gene 66 1-10;Kain, S. R. (1997) Methods. Mol. Biol. 63 49-60), β-galactosidase (See,U.S. Pat. No. 5,070,012, issued Dec. 3, 1991 to Nolan et al., andBronstein, I., et al., (1989) J. Chemilum. Biolum. 4 99-111),chloramphenicol acetyltransferase (See Gorman et al., Mol. Cell Biol.(1982) 2 1044-51), β-glucuronidase, peroxidase, β-lactamase (U.S. Pat.Nos. 5,741,657 and 5,955,604), catalytic antibodies, luciferases (U.S.Pat. Nos. 5,221,623; 5,683,888; 5,674,713; 5,650,289; 5,843,746) andnaturally fluorescent proteins (Tsien, R. Y. (1998) Annu. Rev. Biochem.67 509-44).

The use of chimeras comprising the ligand binding domain (LBD) of thenuclear receptor of interest to a heterologous DNA binding domain (DBD)expands the versatility of cell based assays by directing activation ofthe nuclear receptor in question to defined DNA binding elementsrecognized by defined DNA binding domain (see WO95/18380). This assayexpands the utility of cell based co-transfection assays in cases wherethe biological response or screening window using the native DNA bindingdomain is not satisfactory.

In general the methodology is similar to that used with the basicco-transfection assay, except that a chimeric construct is used in placeof the full length nuclear receptor. As with the full length nuclearreceptor, treatment of the transfected cells with an agonist for thenuclear receptor LBD increases the transcriptional activity of theheterologous DNA binding domain which is reflected by an increase inexpression of the reporter gene as described above. Typically for suchchimeric constructs, the DNA binding domains from defined nuclearreceptors, or from yeast or bacterially derived transcriptionalregulators such as members of the GAL 4 and Lex A/Umud super familiesare used.

A third cell based assay of utility for screening compounds of thepresent invention is a mammalian two-hybrid assay that measures theability of the nuclear hormone receptor to interact with a cofactor inthe presence of a ligand. (See for example, U.S. Pat. Nos. 5,667,973,5,283,173 and 5,468,614). The basic approach is to create three plasmidconstructs that enable the interaction of the nuclear receptor with theinteracting protein to be coupled to a transcriptional readout within aliving cell. The first construct is an expression plasmid for expressinga fusion protein comprising the interacting protein, or a portion ofthat protein containing the interacting domain, fused to a GAL4 DNAbinding domain. The second expression plasmid comprises DNA encoding thenuclear receptor of interest fused to a strong transcription activationdomain such as VP16, and the third construct comprises the reporterplasmid comprising a reporter gene with a minimal promoter and GAL4upstream activating sequences.

Once all three plasmids are introduced into a cell, the GAL4 DNA bindingdomain encoded in the first construct allows for specific binding of thefusion protein to GAL4 sites upstream of a minimal promoter. Howeverbecause the GAL4 DNA binding domain typically has no strongtranscriptional activation properties in isolation, expression of thereporter gene occurs only at a low level. In the presence of a ligand,the nuclear receptor-VP16 fusion protein can bind to theGAL4-interacting protein fusion protein bringing the strongtranscriptional activator VPP16 in close proximity to the GAL4 bindingsites and minimal promoter region of the reporter gene. This interactionsignificantly enhances the transcription of the reporter gene, which canbe measured for various reporter genes as described above. Transcriptionof the reporter gene is thus driven by the interaction of theinteracting protein and nuclear receptor of interest in a liganddependent fashion.

Any compound which is a candidate for activation of FXR may be tested bythese methods. Generally, compounds are tested at several differentconcentrations to optimize the chances that activation of the receptorwill be detected and recognized if present. Typically assays areperformed in triplicate and vary within experimental error by less than15%. Each experiment is typically repeated three or more times withsimilar results.

Activity of the reporter gene can be conveniently normalized to theinternal control and the data plotted as fold activation relative tountreated cells. A positive control compound (agonist) may be includedalong with DMSO as high and low controls for normalization of the assaydata. Similarly, antagonist activity can be measured by determining theability of a compound to competitively inhibit the activity of anagonist.

Additionally the compounds and compositions can be evaluated for theirability to increase or decrease the expression of genes known to bemodulated by FXR and other nuclear receptors in vivo, usingNorthern-blot, RT PCR or oligonucleotide microarray analysis to analyzeRNA levels. Western-blot analysis can be used to measure expression ofproteins encoded by FXR target genes. Genes that are known to beregulated by the FXR include cholesterol 7 α-hydroxylase (CYP7A1), therate limiting enzyme in the conversion of cholesterol to bile acids, thesmall heterodimer partner-1 (SHP-1), the bile salt export pump (BSEP,ABCB11), canalicular bile acid export protein, sodium taurocholatecotransporting polypeptide (NTCP, SLC10A1) and intestinal bile acidbinding protein (I-BABP).

Established animal models exist for a number of diseases of directrelevance to the claimed compounds and these can be used to furtherprofile and characterize the claimed compounds. These model systemsinclude diabetic dislipidemia using Zucker (fa/fa) rats or (db/db) mice,spontaneous hyperlipidemia using apolipoprotein E deficient mice(ApoE^(−/−)), diet-induced hyperlipidemia, using low density lipoproteinreceptor deficient mice (LDR^(−/−)) and atherosclerosis using both theApo E(^(−/−)) and LDL(^(−/−)) mice fed a western diet. (21% fat, 0.05%cholesterol). Additionally FXR or LXR animal models (e.g., knockoutmice) can be used to further evaluate the present compounds andcompositions in vivo (see, for example, Sinai, et al., Cell, 102:731-744 (2000), Peet, et al., Cell, 93:693-704 (1998)).

F. Methods of Use of the Compounds and Compositions

Methods of use of the compounds and compositions provided hereincompounds and compositions for altering nuclear receptor activity,including FXR and/or orphan nuclear receptor activity, and fortreatment, prevention, or amelioration of one or more symptoms ofdiseases or disorder that are modulated by nuclear receptor activity,including FXR and/or orphan nuclear receptor activity, or in whichnuclear receptor activity, including FXR and/or orphan nuclear receptoractivity, is implicated.

Methods of altering nuclear receptor activity, including FXR, and/ororphan nuclear receptor activity, by contacting the receptor with one ormore compounds or compositions provided herein, are provided.

Methods of reducing cholesterol levels and of modulating cholesterolmetabolism, catabolism, absorption of dietary cholesterol (see, e.g.,International Patent Application Publication No. 00/40965) and reversecholesterol transport (see, e.g., International Patent ApplicationPublication No. WO 00/78972), all of which implicate FXR activity, areprovided. Also provided are methods of increasing the expression ofATP-Binding Cassette (ABC1) in mammalian cells using the compounds andcompositions provided herein (see, e.g., International PatentApplication Publication No. WO 00/78972).

Methods of treatment, prevention, or amelioration of one or moresymptoms of a disease or disorder affecting cholesterol, triglyceride,or bile acid levels are provided using the compounds and compositionsprovided herein. Also provided are methods of treatment, prevention, oramelioration of one or more symptoms of a disease or disorder affectinglipid metabolism (i.e., lipodystrophy).

Methods of treatment, prevention, or amelioration of one or more formsof hyperlipidemia, including hypercholesterolemia (see, e.g.,International Patent Application Publication No. WO 00/57915);hyperlipoproteinemia (see, e.g., International Patent ApplicationPublication No. WO 01/60818) and hypertriglyceridemia are provided. Theterm “hyperlipidemia” refers to the presence of an abnormally elevatedlevel of lipids in the blood. Hyperlipidemia can appear in at leastthree forms: (1) hypercholesterolemia, i.e., an elevated cholesterollevel; (2) hypertriglyceridemia, i.e., an elevated triglyceride level;and (3) combined hyperlipidemia, i.e., a combination ofhypercholesterolemia and hypertriglyceridemia.

Methods are also provided for the treatment, prevention, or ameliorationof a number of disease states associated with elevated cholesterollevels, including coronary artery disease, angina pectoris, carotidartery disease, strokes, cerebral arteriosclerosis, and xanthoma.

Methods of treatment, prevention, or amelioration of one or moresymptoms of dyslipidemia are provided herein. The term “dyslipidemia”refers to abnormal levels of lipoproteins in blood plasma including bothdepressed and/or elevated levels of lipoproteins (e.g., elevated levelsof LDL, VLDL and depressed levels of HDL).

Methods of treatment, prevention, or amelioration of hyperglycemia ordiabetes mellitus (see, e.g., International Patent ApplicationPublication No. WO 01/82917) are also provided using the compounds andcompositions provided herein. Diabetes mellitus, commonly calleddiabetes, refers to a disease or condition that is generallycharacterized by metabolic defects in production and utilization ofglucose which result in the failure to maintain appropriate blood sugarlevels in the body (see, e.g., LeRoith, D. et al., (eds.), DIABETESMELLITUS (Lippincott-Raven Publishers, Philadelphia, Pa. U.S.A. 1996)).

In the case of diabetes of the type 2 form, the disease is characterizedby insulin resistance, in which insulin loses its ability to exert itsbiological effects across a broad range of concentrations. Thisresistance to insulin responsiveness results in insufficient insulinactivation of glucose uptake, oxidation and storage in muscle andinadequate insulin repression of lipolysis in adipose tissue and ofglucose production and secretion in liver (see, e.g., Reaven, G. M., J.Basic & Clin. Phys. & Phami. (1998) 9: 387-406 and Flier, J. Ann Rev.Med. (1983) 34:145-60). The resulting condition is elevated bloodglucose, which is called “hyperglycemia.” Uncontrolled hyperglycemia isassociated with increased and premature mortality due to an increasedrisk for microvascular and macrovascular diseases, including retinopathy(the impairment or loss of vision due to blood vessel damage in theeyes); neuropathy (nerve damage and foot problems due to blood vesseldamage to the nervous system); and nephropathy (kidney disease due toblood vessel damage in the kidneys), hypertension, cerebrovasculardisease and coronary heart disease. Therefore, control of glucosehomeostasis is a critically important approach for the treatment ofdiabetes.

Insulin resistance has been hypothesized to unify the clustering ofhypertension, glucose intolerance, hyperinsulinemia, increased levels oftriglyceride and decreased HDL cholesterol, and central and overallobesity. The association of insulin resistance with glucose intolerance,an increase in plasma triglyceride and a decrease in high-densitylipoprotein cholesterol concentrations, hypertension, hyperuricemia,smaller denser low-density lipoprotein particles, and higher circulatinglevels of plasminogen activator inhibitor-1, has been referred to as“Syndrome X” (see, e.g., Reaven, G. M., Physiol. Rev. (1995) 75:473-486). Accordingly, methods of treatment, prevention, or ameliorationof any disorders related to insulin resistance including the cluster ofdisease states, conditions or disorders that make up “Syndrome X” areprovided.

Methods of treatment, prevention, or amelioration of obesity,atherosclerosis, lipid disorders, cardiovascular disorders, or gallstonedisease (see, e.g., International Patent Application Publication No. WO00/37077); acne vulgaris or acneiform skin conditions (see, e.g.,International Patent Application Publication No. WO 00/49992);Parkinson's disease, inflammation, immunological disorders, cancer orAlzheimer's disease (see, e.g., International Patent ApplicationPublication No. WO 00/17334); conditions characterized by a perturbedepidermal barrier function, peripheral occlusive disease, ischemicstroke, or conditions of disturbed differentiation or excessproliferation of the epidermis or mucous membrane (see, e.g., U.S. Pat.Nos; 6,184,215 and 6,187,814, and International Patent ApplicationPublication No. WO 98/32444) are provided.

Further provided herein are methods for the treatment, prevention, oramelioration of one or more symptoms of cholestasis, as well as for thetreatment of the complications of cholestasis by administering acompound provided herein.

Cholestasis is typically caused by factors within the liver(intrahepatic) or outside the liver (extrahepatic) and leads to theaccumulation of bile salts, bile pigment bilirubin, and lipids in theblood stream instead of being eliminated normally.

Intrahepatic cholestasis is characterized by widespread blockage ofsmall ducts or by disorders, such as hepatitis, that impair the body'sability to eliminate bile. Intrahepatic cholestasis may also be causedby alcoholic liver disease, primary biliary cirrhosis, cancer that hasspread (metastasized) from another part of the body, primary sclerosingcholangitis, gallstones, biliary colic and acute cholecystitis. It canalso occur as a complication of surgery, serious injury, cysticfibrosis, infection, or intravenous feeding or be drug induced.Cholestasis may also occur as a complication of pregnancy and oftendevelops during the second and third trimesters.

Extrahepatic cholestasis is most often caused by choledocholithiasis(Bile Duct Stones), benign biliary strictures (non-cancerous narrowingof the common duct), cholangiocarcinoma (ductal carcinoma) andpancreatic carcinoma. Extrahepatic cholestasis can occur as a sideeffect of many medications.

Accordingly, compounds provided herein may be used for the treatment,prevention, or amelioration of one or more symptoms of intrahepatic orextrahepatic cholestasis, including without limitation, biliary artesia,obstetric cholestasis, neonatal cholestasis, drug induced cholestasis,cholestasis arising from Hepatitis C infection, chronic cholestaticliver disease such as primary binary cirrhosis (PBC) and primarysclerosing cholangitis (PSC).

Further provided by this invention are methods for treating obesity, aswell as treating the complications of obesity, by administering acompound of the present invention. The terms “obese” and “obesity”refers to, according to the World Health Organization, a Body Mass Index(BMI) greater than 27.8 kg/m² for men and 27.3 kg/m² for women (BMIequals weight (kg)/height (m). Obesity is linked to a variety of medicalconditions including diabetes and hyperlipidemia. Obesity is also aknown risk factor for the development of type 2 diabetes (See, e.g.,Barrett-Conner, E, Epidemol. Rev. (1989) 11: 172-181; and Knowler, etal., Am. J. Clin. Nutr. (1991) 53:1543-1551).

The compounds or composition that may be used for treating obesity orits complications, can be identified, formulated, and administered aspreviously described above. Such a compound or composition will compriseeither a FXR selective antagonist a partial agonist/antagonist orantagonist that exhibits about a two to about a ten-fold preference forFXR compared to another nuclear receptor such as, for example LXR α or βwith respect to potency (IC₅₀, the concentration of compound thatachieves 50% of the maximum reduction in the transcription activityachieved by the compound of interest observed in the presence of asub-maximal concentration of FXR agonist) and/or efficacy (the maximumpercent inhibition of transcription observed with the compound inquestion).

G. Combination Therapy

Also contemplated herein is combination therapy using a compoundprovided herein, or a pharmaceutically acceptable derivative thereof, incombination with one or more of the following: antihyperlipidemicagents, plasma HDL-raising agents, antihypercholesterolemic agents,cholesterol biosynthesis inhibitors (such as HMG CoA reductaseinhibitors, such as lovastatin, simvastatin, pravastatin, fluvastatin,atorvastatin and rivastatin), acyl-coenzyme A:cholesterol acytransferase(ACAT) inhibitors, probucol, raloxifene, nicotinic acid, niacinamide,cholesterol absorption inhibitors, bile acid sequestrants (such as anionexchange resins, or quaternary amines (e.g., cholestyramine orcolestipol)), low density lipoprotein receptor inducers, clofibrate,fenofibrate, benzofibrate, cipofibrate, gemfibrizol, vitamin B₆, vitaminB₁₂, anti-oxidant vitamins, β-blockers, anti-diabetes agents,angiotensin II antagonists, angiotensin converting enzyme inhibitors,platelet aggregation inhibitors, fibrinogen receptor antagonists, LXR αor β, agonists, antagonists or partial agonists, aspirin or fibric acidderivatives. The compound provided herein, or pharmaceuticallyacceptable derivative thereof, is administered simultaneously with,prior to, or after administration of one or more of the above agents.Pharmaceutical compositions containing a compound provided herein andone or more of the above agents are also provided.

Combination therapy includes administration of a single pharmaceuticaldosage formulation which contains a FXR selective compound and one ormore additional active agents, as well as administration of the FXRselective compound and each active agent in its own separatepharmaceutical dosage formulation. For example, a FXR agonist orantagonist of the present invention and an HMG-CoA reductase inhibitorcan be administered to the patient together in a single oral dosagecomposition such as a tablet or capsule, or each agent administered inseparate oral dosage formulations. Where separate dosage formulationsare used, the compounds described herein and one or more additionalactive agents can be administered at essentially the same time, i.e.,concurrently, or at separately staggered times, i.e., sequentially;combination therapy is understood to include all these regimens.

The compound is preferably administered with a cholesterol biosynthesisinhibitor, particularly arm HMG-CoA reductase inhibitor. The termHMG-CoA reductase inhibitor is intended to include all pharmaceuticallyacceptable salt, ester, free acid and lactone forms of compounds whichhave HMG-CoA reductase inhibitory activity and, therefore, the use ofsuch salts, esters, free acids and lactone forms is included within thescope of this invention. Compounds which have inhibitory activity forHMG-CoA reductase can be readily identified using assays well-known inthe art. For instance, suitable assays are described or disclosed inU.S. Pat. No. 4,231,938 and WO 84/02131. Examples of suitable HMG-OAreductase inhibitors include, but are not limited to, lovastatin(MEVACOR®; see, U.S. Pat. No. 4,231,938); simvastatin (ZOCOR®; see, U.S.Pat. No. 4,444,784); pravastatin sodium (PRAVACHOL®; see, U.S. Pat. No.4,346,227); fluvastatin sodium (LESCOL®; see, U.S. Pat. No. 5,354,772);atorvastatin calcium (LIPITOR®; see, U.S. Pat. No. 5,273,995) andrivastatin (also known as cerivastatin; see, U.S. Pat. No. 5,177,080).The structural formulas of these and additional HMG-CoA reductaseinhibitors that can be used in the methods of the present invention aredescribed at page 87 of M. Yalpani, “Cholesterol Lowering Drugs,”Chemistry & Industry, pp. 85-89 (5 Feb. 1996). In presently preferredembodiments, the HMG-CoA reductase inhibitor is selected from lovastatinand simvastatin.

Dosage information for HMG-CoA reductase inhibitors is well known in theart, since several HMG-CoA reductase inhibitors are marketed in the U.S.In particular, the daily dosage amounts of the HMG-CoA reductaseinhibitor may be the same or similar to those amounts which are employedfor anti-hypercholesterolemic treatment and which are described in thePhysicians' Desk Reference (PDR). For example, see the 50th Ed. of thePDR, 1996 (Medical Economics Co); in particular, see at page 216 theheading “Hypolipidemics,” sub-heading “HMG-CoA Reductase Inhibitors,”and the reference pages cited therein. Preferably, the oral dosageamount of HMG-CoA reductase inhibitor is from about 1 to 200 mg/day and,more preferably, from about 5 to 160 mg/day. However, dosage amountswill vary depending on the potency of the specific HMG-CoA reductaseinhibitor used as well as other factors as noted above. An HMG-CoAreductase inhibitor which has sufficiently greater potency may be givenin sub-milligram daily dosages.

As examples, the daily dosage amount for simvastatin may be selectedfrom 5 mg, 10 mg, 20 mg, 40 mg, 80 mg and 160 mg for lovastatin, 10 mg,20 mg, 40 mg and 80 mg; for fluvastatin sodium, 20 mg, 40 mg and 80 mg;and for pravastatin sodium, 10 mg, 20 mg, and 40 mg. The daily dosageamount for atorvastatin calcium may be in the range of from 1 mg to 160mg and, more particularly, from 5 mg to 80 mg. Oral administration maybe in a single or divided doses of two, three, or four times daily,although a single daily dose of the HMG-CoA reductase inhibitor ispreferred.

Diabetic patients are likely suffer from premature development ofatherosclerosis and increased rate of cardiovascular and peripheralvascular diseases. Hyperlipidemia and dyslipidemia are importantprecipitating factors for these diseases. Hyperlipidemia is a conditiongenerally characterized by an abnormal increase in serum lipids (e.g.triglycerides and cholesterol) in the bloodstream and is an importantrisk factor in developing atherosclerosis and heart disease. See, e.g.,Wilson, J. et al., (ed.), Disorders of Lipid Metabolism, Chapter 23,Textbook of Endocrinology, 9th Edition, (W. B. Sanders Company,Philadelphia, Pa. U.S.A. 1998). Dyslipidemia is an abnormal levels oflipoproteins in blood plasma (e.g. elevated levels of LDL, VLDL anddepressed levels of HDL), and has been shown to be one of the maincontributors to the increased incidence of coronary events and deathsamong diabetic subjects (see, e.g., Joslin, E. Ann. Chim. Med. (1927) δ:1061-1079). Epidemiological studies since then have confirmed theassociation and have shown a several-fold increase in coronary deathsamong diabetic subjects when compared with nondiabetic subjects (see,e.g., Garcia, M. J. et al., Diabetes (1974) 23: 105-11 (1974); andLaakso, M. and Lehto, S., Diabetes Reviews (1997) 5(4): 294-315).

The methods of the present invention can be used effectively incombination with one or more additional active anti-diabetes agentsdepending on the desired target therapy (see, e.g., Turner, N. et al.,Prog. Drug Res. (1998) 51: 33-94; Haffner, S., Diabetes Care (1998) 21:160-178; and DeFronzo, R. et al., (eds.), Diabetes Reviews (1997) Vol. 5No. 4). A number of studies have investigated the benefits ofcombination therapies with oral agents (see, e.g., Mahler, R., J. Clin.Endocrinol. Metab. (1999) 84:1165-71; United Kingdom ProspectiveDiabetes Study Group: UKPDS 28, Diabetes Care (1998) 21: 87-92; Bardin,C. W.,(ed.), CURRENT THERAPY IN ENDOCRINOLOGY AND METABOLISM, 6thEdition (Mosby-Year Book, Inc., St. Louis, Mo. 1997); Chiasson, J. etal., Ann. Intern. Med. (1994) 121: 928-935; Coniff, R. et al., Clin.Ther. (1997) 19: 1626; Coniff, R. et al., Am. J. Med. (1995) 98:443-451; and Iwamoto, Y. et al, Diabet. Med. (1996) 13 365-370;Kwiterovich, P. Am. J. Cardiol (1998) 82(12A): 3U-17U). These studiesindicate that diabetes and hyperlipidemia modulation can be furtherimproved by the addition of a second agent to the therapeutic regimen.

An example of combination therapy that modulates (prevents the onset ofthe symptoms or complications associated) atherosclerosis, isadministered with one or more of the following active agents: anantihyperlipidemic agent; a plasma HDL-raising agent, anantihypercholesterolemic agent, such as a cholesterol biosynthesisinhibitor, e.g., an hydroxymethylglutaryl (HMG) CoA reductase inhibitor(also referred to as statins, such as lovastatin, simvastatin,pravastatin, fluvastatin, and atorvastatin), an HMG-CoA synthaseinhibitor, a squalene epoxidase inhibitor, or a squalene synthetaseinhibitor (also known as squalene synthase inhibitor); an acyl-coenzymeA cholesterol acyltransferase (ACAT) inhibitor, such as melinamide;probucol; nicotinic acid and the salts thereof and niacinamide; acholesterol absorption inhibitor, such as β-sitosterol; a bile acidsequestrant anion exchange resin, such as cholestyramine, colestipol ordialkylaminoalkyl derivatives of a cross-linked dextran; an LDL (lowdensity lipoprotein) receptor inducer; fibrates, such as clofibrate,bezafibrate, fenofibrate, and gemfibrizol; vitamin B₆ (also known aspyridoxine) and the pharmaceutically acceptable salts thereof, such asthe HCl salt; vitamin B₁₂ (also known as cyanocobalamin); vitamin E₃(also known as nicotinic add and niacinamide, supra); anti-oxidantvitamins, such as vitamin C and E and beta carotene; a beta-blocker; LXRα or βagonists, antagonists, or partial agonists, an angiotensin IIantagonist; an angiotensin converting enzyme inhibitor; and a plateletaggregation inhibitor, such as fibrinogen receptor antagonists (i.e.,glycoprotein IIb/IIIa fibrinogen receptor antagonists) and aspirin.

Still another example of combination therapy can be seen in modulatingdiabetes (or treating diabetes and its related symptoms, complications,and disorders) with, for example, sulfonylureas (such as chlorpropamide,tolbutamide, acetohexamide, tolazamide, glyburide, gliclazide, glynase,glimepiride, and glipizide), biguanides (such as metformin),thiazolidinediones (such as ciglitazone, pioglitazone, troglitazone, androsiglitazone); and related insulin sensitizers, such as selective andnon-selective activators of PPARα PPARβ and PPARγ;dehydroepiandrosterone (also referred to as DHEA or its conjugatedsulphate ester, DHEA-SO₄); antiglucocorticoids; TNFα inhibitors;α-glucosidase inhibitors (such as acarbose, miglitol, and voglibose),pramlintide (a synthetic analog of the human hormone amylin), otherinsulin secretogogues (such as repaglinide, gliquidone, andnateglinide), insulin, as well as the active agents discussed above fortreating atherosclerosis.

Another example of combination therapy is the co-administration of thecompound or composition provided herein with compounds or compositionfor treating obesity or obesity-related disorders, wherein the methodscan be effectively used in combination with, for example,phenylpropanolamine, phentermine, diethylpropion, mazindol;fenfluramine, dexfenfluramine, phentiramine, β₃ adrenoceptor agonistagents; sibutramine, gastrointestinal lipase inhibitors (such asorlistat), LXR α or β agonists, antagonists and partial agonists, andleptins. Other agents used in treating obesity or obesity-relateddisorders include neuropeptide Y, enterostatin, cholecytokinin,bombesin, amylin, histamine H₃ receptors, dopamine D₂ receptors,melanocyte stimulating hormone, corticotrophin releasing factor, galaninand gamma amino butyric acid (GABA).

Another example of a combination therapy can be seen in treatingcholestasis, where the compounds of the invention can be combined withActigall (Ursodeoxycholic acid—UDCA), corticosteroids, anti-infectiveagents (Rifampin, Rifadin, Rimactane), anti-viral agents, Vitamin D,Vitamin A, phenobarbital, cholestyramine, UV light, antihistamines, oralopiate receptor antagonists and biphosphates, for the treatment,prevention, or amelioration of one or more symptoms of intrahepatic orextrahepatic cholestasis. Dosage information for these agents is wellknown in the art.

The following examples are included for illustrative purposes only andare not intended to limit the scope of the invention. Starting materialsin the synthesis examples below are either available from commercialsources or via literature procedures. All commercially availablecompounds were used without further purification unless otherwiseindicated. CDCl₃ (99.8% D, Cambridge Isotope Laboratories) was used inall experiments as indicated. Proton (¹H) nuclear magnetic resonance(NMR) spectra were recorded on a Bruker Avance 400 MHz NMR spectrometer.Significant peaks are tabulated and typically include: number ofprotons, multiplicity (s, singlet; d, double; t, triplet; q, quartet; m,multiplet; br s, broad singlet). Chemical shifts are reported as partsper million (6) relative to tetramethylsilane. Low resolution massspectra (MS) were obtained as electrospray ionization (ESI) massspectra, which were recorded on a Perkin-Elmer SCIEX HPLC/MS instrumentusing reverse-phase conditions (acetonitrile/water, 0.05%trifluoroacetic acid). Flash chromatography was performed using MerckSilica Gel 60 (230-400 mesh) following standard protocol (Still et al.J. Orb. Chem. 1978, 43, 2923).

Example 1 Preparation of 2-(2-Chloropropionylamino)Benzoic Acid MethylEster and Related Compounds

A. To methyl anthranilate (5 g, 33.1 mmol) stirring in DCM at 0° C.under N₂ was added DIEA (5.1 g, 39.7 mmol) in one portion followed bythe dropwise addition of 2-chloropropionyl chloride (4.2 g, 33.1 mmol).The reaction was allowed to stir at 0° C. for 30 min. then warmed toroom temperature, stirring for an additional 3 h. The reaction wastreated with saturated aqueous solution of NaHCO₃ and the resultingbiphasic mixture transferred to a separatory funnel. The layersseparated and the aqueous layer was extracted twice more with DCM (25mL). The combined organic layers were washed with brine, dried overMgSO₄ and concentrated under vacuum to afford the desired product (7.75g, 97% yield), which was used without further purification. ¹H-NMR(CDCl₃): δ 11.8 (br, 1H), 8.72 (dd, 1H), 8.08 (dd, 1H), 7.58 (m, 1H),7.15 (m, 1H), 4.56 (q, 1H), 3.97 (s, 3H), 1.85 (d, 3H).

B. In a similar manner, but replacing methyl anthranilate with2-amino-5-bromobenzoic acid methyl ester, the following compound wasprepared:

5-bromo-2-(2-chloro-propionylamino)-benzoic acid methyl ester; ¹H-NMR(CDCl₃): δ 11.77 (broad, 1H), 8.64 (d, 1H), 8.18 (d, 1H), 7.65 (dd, 1H),4.53 (q, 1H), 3.97 (s, 3H), 1.82 (d, 3H); MS (ESI) 320 (MH⁺).

Example 2 Preparation of 2-(2-Chloropropionylamino)Benzoic Acid

To the 2-(2-chloro-propionylamino)-benzoic acid methyl ester (7.75 g,32.1 mmol) stirring in THF (40 mL) was added 1 M LiOH/H₂O (40 mL). Thereaction was allowed to stir at 50° C. for 3 h. After this period thereaction was concentrated under vacuum to afford a crude residue thatwas acidified with 1 N HCl. The resulting suspension was then dilutedwith EtOAc and washed with water (3×50 mL). The organic layer was thenwashed with brine (25 mL), dried over MgSO₄, and concentrated undervacuum to afford crude acid. The crude material was purified by flashchromatography (silica gel, 80% EtOAc/Hex) to afford the desired productas an off white solid (7.1 g, 97% yield). ¹H-NMR (CDCl₃): δ 8.6 (d, 1H),8.12 (d, 1H), 7.61 (t, 1H), 7.57 (t, 1H), 4.89 (br, 1H), 4.65 (t, 1H),1.78 (d, 3H).

Example 3 Preparation of2-(1-chloroethyl)-3-(4-methoxyphenyl)-3H-quinazolin-4-one and RelatedCompounds

A. To a stirring suspension of 2-(2-chloropropionylamino)-benzoic acid(5 g, 22 mmol) and p-anisidine (2.7 g, 22 mmol) in 100 mL of toluene wasadded dropwise phosphorus trichloride (PCl₃) (3.02 g, 22 mmol) over 15minutes. When the addition was complete the reaction was heated toreflux for 3 h and cooled to room temperature and treated with 5 mLwater. The resulting mixture was concentrated under vacuum to yield asemi-solid residue that was treated with 1 N HCl and extracted twicewith 200 mL portions of EtOAc. The organic extracts were combined,washed with brine, dried over MgSO₄, and concentrated under vacuum toafford crude product that was purified by column chromatography (silicagel, EtOAc/Hex 4:1) (4.96 g, 72% yield). ¹H-NMR (CDCl₃): δ 8.31 (m, 1H),7.82 (m, 2H), 7.54 (m, 1H), 7.43 (dd, 1H), 7.09 (m, 3H), 4.66 (q, 1H),3.91 (s, 3H), 1.89 (d, 3H).

B. In a similar manner, but replacing p-anisidine with the appropriatestarting material, the following compounds were made:

2-(1-chloroethyl)-3-(4-methylphenyl)-3H-quinazolin-4-one; ¹H-NMR(CDCl₃): δ 8.29 (d, 1H), 7.80 (d, 2H), 7.52 (m, 1H), 7.38 (s, 2H), 7.34(d, 1H), 7.07 (m, 1H), 4.62 (q, 11H), 2.46 (s, 3H), 1.87 (d, 3H); MS(ESI) 299 (MH⁺);

3-(4-bromophenyl)-2-(1-chloroethyl)-3H-quinazolin-4-one; ¹H-NMR (CDCl₃):δ 8.28 (d, 1H), 7.81 (m, 2H), 7.70 (m, 2H), 7.54 (m, 1H), 7.39 (m, 1H),7.08 (m, 1H), 4.55 (q, 1H), 1.88 (d, 3H); MS (ESI) 365 (MH⁺); and

2-(1-chloroethyl)-3-(2,4-dimethylphenyl)-3H-quinazolin-4-one; ¹H-NMR(CDCl₃): δ 8.33 (d, 1H), 7.83 (m, 2H), 7.54 (m, 1H), 7.26 (m, 2H), 6.95(d, 1H), 4.73 (q, 1H), 2.44 (s, 3H), 2.22 (s, 1.5H), 2.06 (s, 1.5H),1.89 (m, 1H); MS (ESI) 313 (MH⁺).

C. In a similar manner as described above in Paragraph A, but replacing2-(2-chloropropionylamino)benzoic acid with5-bromo-2-(2-chloro-propionylamino)benzoic acid and p-anisidine with4-methyl-phenylamine, the following compound was prepared:

6-bromo-2-(1-chloroethyl)-3-p-tolyl-3H-quinolin-4-one; ¹H-NMR (CDCl₃): δ8.40 (m, 1H), 7.87 (m, 1H), 7.67 (d, 1H), 7.37 (m, 3H), 7.04 (m, 1H),4.59 (q, 1H), 2.46 (s, 3H), 1.84 (d, 3H); MS (ESI) 377 (MH⁺).

Example 4 Preparation of[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-Ylmethyl]-CarbamicAcid Benzyl Ester and Related Compounds

A. To a stirring suspension of2-(2-benzyloxycarbonylamino-acetylamino)-benzoic acid (2 g, 6.1 mmol) inTHF (100 mL) was added carbonyldiimidizole (CDI) (1.0 g, 6.2 mmol) andstirred for 1 h at room temperature under a nitrogen atmosphere. After 1h the reaction was treated with p-anisidine (0.73 g, 6.1 mmol) andrefluxed for 16 h. The reaction was cooled to room temperature andconcentrated under vacuum to afford a crude residue that was dissolvedin EtOAc (50 mL). The mixture was then washed with saturated NaHCO₃ (50mL) followed with brine (25 mL). The organic layer was dried over MgSO₄and concentrated under vacuum to afford crude product that was purifiedby flash chromatography (silica gel, EtOAc/Hex4:1) (1.21 g, 48% yield).¹H-NMR (CDCl₃): δ 8.26 (m, 1H), 7.72 (m, 2H), 7.47 (m, 1H), 7.34 (m,5H), 7.19 (m, 2H), 7.03 (m, 2H), 6.28 (broad, 1H), 5.10 (s, 2H), 4.50(s, 2H), 3.85 (s, 3H).

B. In a similar manner, but replacing p-anisidine with2,4-dimethylaniline, the following compound was made:

-   [3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-carbamic    acid benzyl ester; MS (ESI) 414 (MH⁺).

Example 5 Preparation of3-(4-methoxyphenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one andRelated Compounds

A. To the neat 2-(1-chloroethyl)-3-(4-methoxyphenyl)-3H-quinazolin-4-one(1.0 g, 3.2 mmol) in a sealed tube was added 40 mL of a methylaminesolution (1 M in THF, 40 mmol). The tube was sealed and heated to 110°C. 16 h. The resulting solution was cooled to room temperature andconcentrated under vacuum to afford the crude product that was purifiedby flash chromatography (5% MeOH/DCM, silica gel) to afford the titlecompound (yield 0.97 g, 99%). ¹H-NMR (CD₃OD): δ 8.28 (m, 1H), 7.93 (m,1H), 7.86 (m, 1H), 7.65 (m, 1H), 7.43 (m, 1H) 7.33 (m, 1H), 7.19 (m,2H), 4.09 (q, 1H), 3.92 (s, 3H), 2.75 (s, 3H), 1.51 (d, 3H).

B. In a similar manner, but replacing2-(1-chloroethyl)-3-(4-methoxyphenyl)-3H-quinazolin-4-one with theappropriate starting material, the following compounds were made:

2-(1-methylaminoethyl)-3p-tolyl-3H-quinazolin-4-one; ¹H-NMR (CD₃OD): δ8.28 (d, 1H), 7.77 (m, 1H), 7.71 (m, 1H), 7.47 (m, 1H), 7.36 (m, 2H),7.12 (m, 2H), 3.37 (q, 1H), 2.46 (s, 3H), 2.28 (s, 3H), 1.24 (d, 3H); MS(ESI) 294 (MH⁺);

6-bromo-2-(1-methylaminoethyl)-3-p-tolyl-3H-quinazolin-4-one; ¹H-NMR(CD₃OD): δ 8.39 (d, 1H), 7.84 (m, 1H), 7.59 (d, 1H), 7.37 (m, 2H), 7.11(m, 2H), 3.36 (q, 1H), 2.46 (s, 3H), 2.26 (s, 3H), 1.57 (broad, 1H),1.23 (d, 3H); MS (ESI) 317 (MH⁺);

3-(2,4-dimethylphenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one;¹H-NMR (CD₃OD): δ 8.29 (d, 1H), 7.75 (m, 2H), 7.47 (t, 1H), 7.14 (s,1H), 6.85 (d, 2H), 3.38 (q, 1H), 2.39 (s, 6H), 2.29 (s, 3H), 1.25 (d,3H); MS (ESI) 308 (MH⁺); and

3-(4-methoxyphenyl)-2-methylaminomethyl-3H-quinazolin-4-one; ¹H-NMR(CD₃OD): δ 8.27 (d, 1H), 7.93 (m, 1H), 7.86 (d, 1H), 7.65 (t, 1H), 7.43(m, 1H), 7.33 (m, 1H), 7.19 (m, 2H), 4.08 (s, 2H), 3.92 (s, 3H), 2.74(s, 3H); MS (ESI) 296 (MH⁺).

C. In a similar manner, but with the appropriate starting materials, thefollowing compound was made:

3-(4-methoxyphenyl)-8-methyl-2-(1-methylaminoethyl)-3H-quinazolin-4-one;MS (ESI) 324 (MH⁺).

D. In a similar manner as described above in Example 1, but replacingmethyl anthranilate with the appropriate intermediate starting material,and in a similar manner as described above in Paragraph A, the followingcompounds were made:

-   3-(4-methoxyphenyl)-6-methyl-2-(1-methylaminoethyl)-3H-quinazolin-4-one;    MS (ESI) 324 (MH⁺);-   3-(4-methoxyphenyl)-7-methyl-2-(1-methylaminoethyl)-3H-quinazolin-4-one;    MS (ESI) 324 (MH⁺);-   8-methoxy-3-(4-methoxyphenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one;    MS (ESI) 340 (MH⁺);-   5-methoxy-3-(4-methoxyphenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one;    MS (ESI) 340 (MH⁺); and-   6-methoxy-3-(4-methoxyphenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one;    MS (ESI) 340 (MH⁺).

Example 6 Preparation of2-aminomethyl-3-(4-methoxyphenyl)-3H-quinazolin-4-one

In an oven dried flask that was purged with nitrogen was placed3-(4-methyoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-carbamicacid benzyl ester (1.0 g, 2.4 mmol). The starting material was dilutedwith nitrogen sparged EtOH (25 mL) while maintaining a nitrogenatmosphere. To the reaction mixture was added 10% Pd/C (150 mg) and thereaction sealed with a septum. The sealed reaction was then purged withhydrogen by placing a syringe equipped with a balloon full of hydrogengas through the septum. The reaction was stirred vigorously whileinserting an additional needle in the septa to flush the atmosphere withhydrogen. With a full balloon of hydrogen in place the reaction wasallowed to stir for 3 h after which it was concentrated under vacuum toyield crude material that was purified by flash chromatography (silicagel, 10% MeOH/DCM) (yield 0.67 g, 100%). ¹H-NMR (CD₃OD): δ 8.23 (m, 1H),7.87 (m, 1H), 7.80 (m, 1H), 7.56 (m, 1H), 7.13 (m, 2H), 7.01 (m, 2H),3.90 (s, 3H), 3.51 (s, 2H); MS (ESI) 282 (MH⁺).

Example 7 Preparation of4-tert-butyl-N-{1-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-Ethyl}-N-methylbenzenesulfonamideand Related Compounds

A. To a suspension of the3-(4-methoxyphenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one (50 mg,0.16 mmol) stirring in 2 mL DCM was added TEA (19 mg, 0.19 mmol)followed by the addition of neat 4-tert-butyl-benzenesulfonyl chloride(37 mg, 0.16 mmol). The reaction was allowed to stir at room temperaturefor 2 h then treated with PS-tris-amine resin (100 mg). The reaction wasallowed to stand for 15 min at room temperature after which the resinwas removed by filtration. The filtrate was concentrated under vacuum toafford the crude product. The crude residue was purified by flashchromatography (silica gel, 50% EtOAc/Hex) to afford the desired productas an off-white powder (74 mg, 92% yield). ¹H-NMR (CDCl₃): δ 8.15 (d,1H), 7.55 (s, 1H), 7.39 (m, 4H), 7.25 (d, 1H), 7.16 (m, 2H), 7.09 (m,1H), 6.70 (m, 2H), 4.90 (q, 1H), 4.83 (s, 3H), 3.11 (s, 3H), 1.22 (d,3H), 1.09 (s, 9H); MS (ESI) 506 (MH⁺).

B. In a similar manner, but replacing3-(4-methoxyphenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one with theappropriate starting material, the following compounds were prepared:

4-tert-butyl-N-methyl-N-[1-(4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]benzenesulfonamide;¹H-NMR (CDCl₃): δ 8.22 (m, 1H), 7.63 (m, 1H), 7.51 (m, 2H), 7.44 (m,3H), 7.33 (m, 2H), 7.23 (m, 2H), 7.06 (m, 1H), 4.95 (q, 1H), 3.19 (s,3H), 2.48 (s, 3H), 1.30 (d, 3H), 1.16 (s, 9H); MS (ESI) 490 (MH⁺);

4-tert-butyl-N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;(mixture of rotomers) ¹H-NMR (CDCl₃): δ 8.30 (m, 1H), 7.72 (m, 1H), 7.56(m, 4H), 7.38 (m, 2H), 7.30 (m, 2H), 7.21 (m, 1H), 5.03 (m, 1H), 3.15(s, 1.5H), 3.01 (s, 1.5H), 2.47 (s, 1.5H), 2.45 (s, 1.5H), 2.26 (s,1.5H), 2.04 (s, 1.5H), 1.31 (s, 4.5H), 1.24 (m, 3H), 1.21 (s, 4.5H); MS(ESI) 504 (MH⁺);

4-tert-butyl-N-{1-[6-methoxy-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;¹H-NMR (CDCl₃): δ 7.58 (d, 1H), 7.50 (d, 2H), 7.47 (m, 1H), 7.24 (m,4H), 7.17 (m, 1H), 7.06 (m, 2H), 4.96 (q, 1H), 3.90 (s, 3H), 3.88 (s,3H), 3.15 (s, 3H), 1.28 (d, 3H), 1.18 (s, 9H); MS (ESI) 536 (MH⁺);

4-tert-butyl-N-[1-(6-methoxy-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]-N-methylbenzenesulfonamide;¹H-NMR (CDCl₃): δ 7.58 (d, 1H), 7.50 (d, 2H), 7.44 (m, 1H), 7.34 (m,1H), 7.24 (m, 5H), 7.05 (m, 1H), 4.93 (q, 1H), 3.88 (s, 3H), 3.15 (s,3H), 2.48 (s, 3H), 1.28 (d, 3H), 1.18 (s, 9H); MS (ESI) 520 (MH⁺);

4-tert-butyl-N-methyl-N-[1-(4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]benzenesulfonamide;¹H-NMR (CDCl₃): δ 8.22 (m, 1H), 7.63 (m, 1H), 7.51 (m, 2H), 7.44 (m,3H), 7.33 (t, 2H), 7.22 (m, 2H), 7.06 (m, 1H), 4.95 (q, 1H), 3.19 (s,3H), 2.48 (s, 3H), 1.30 (d, 3H), 1.16 (s, 9H); MS (ESI) 490 (MH⁺);

4-tert-butyl-N-methyl-N-[1-(3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl]benzenesulfonamide;¹H-NMR (CDCl₃): δ 8.25 (m, 1H), 7.76 (d, 2H), 7.52 (m, 1H), 7.45 (m,3H), 5.53 (q, 1H), 3.84 (s, 3H), 2.81 (s, 3H), 1.41 (d, 3H), 1.27 (s,9H); MS (ESI) 414 (MH⁺);

4-tert-butyl-N-methyl-N-[1-(4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]-benzamide;¹H-NMR (CDCl₃): δ 8.28 (m, 1H), 7.76 (t, 1H), 7.69 (d, 1H), 7.48 (m,2H), 7.36 (m, 4H), 7.28 (m, 1H), 7.19 (m, 1H), 6.96 (m, 1H), 5.43 (q,1H), 3.10 (s, 3H), 2.41 (s, 3H), 1.49 (d, 3H), 1.31 (s, 9H); MS (ESI)454 (MH⁺); and

N-[1-(6-bromo-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]-4-tert-butyl-N-methylbenzenesulfonamide;MS (ESI) 568 (MH⁺).

C. In a similar manner as described above in Paragraph B, but replacing4-tert-butylbenzenesulfonyl chloride with the appropriate startingmaterial, the following compounds were made:

N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-isopropyl-N-methylbenzenesulfonamide;(mixture of rotomers) ¹H-NMR (CDCl₃): δ 8.26 (m, 1H), 7.71 (m, 1H), 7.51(m, 4H), 7.34 (m, 2H), 7.18 (m, 3H), 5.0 (m, 1H), 3.11 (s, 1.5H), 2.97(s, 1.5H), 2.85 (m, 1H), 2.44 (s, 1.5H), 2.42 (s, 1.5H), 2.19 (s, 1.5H),2.01 (s, 1.5H), 1.21 (m, 6H), 1.12 (m, 3H); MS (ESI) 490 (MH⁺);

biphenyl-4-sulfonic acid{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;(mixture of rotomers) ¹H-NMR (CDCl₃): δ 8.27 (m, 1H), 7.68 (m, 3H), 7.56(m, 6H), 7.31 (m, 1H), 7.19 (m, 1H), 6.98 (m, 1H), 5.04 (m, 1H), 3.17(s, 1.5H), 3.03 (s, 1.5H), 2.45 (s, 1.5H), 2.44 (s, 1.5H), 2.22 (s,1.5H), 2.02 (s, 1.5H), 1.24 (m, 3H); MS (ESI) 524 (MH⁺);

quinoline-8-sulfonic acid {1-[3-(2,4-dimethylphenyl)-4-oxo-3,4dihydroquinazolin-2-yl]ethyl}methylamide; (mixture of rotomers) ¹H-NMR(CDCl₃): δ 8.56 (m, 1H), 8.49 (m, 0.5H), 8.34 (m, 1H), 8.19 (m, 1H),7.97 (m, 1H), 7.89 (m, 0.5H), 7.77 (m, 1H), 7.54 (m, 3H), 7.40 (m, 1H),7.31 (m, 1H), 7.22 (m, 1H), 7.10 (m, 1H), 5.66 (m, 1H), 3.32 (s, 3H),2.48 (m, 3H), 2.10 (m, 3H), 1.18 (m, 3H); MS (ESI) 499 (MH⁺);

-   N-[1-(6-bromo-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethy]-4-isopropyl-N-methylbenzenesulfonamide;    MS (ESI) 554 (MH⁺);-   biphenyl-4-sulfonic acid [1-(6-bromo-4-oxo-3-p-tolyl-3,4    dihydroquinazolin-2-yl)ethyl]methylamide; MS (ESI) 588 (MH⁺);-   benzo[1,3]dioxole-5-carboxylic acid [1-(6-bromo-4-oxo-3-p-tolyl-3,4    dihydroquinazolin-2-yl)ethyl]methylamide; MS (ESI) 520 (MH⁺); and-   N-[1-(6-bromo-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]-4-tert-butyl-N-methylbenzamide;    MS (ESI) 532 (MH⁺).

D. In a similar manner as described above in Paragraph A, but replacing4-tert-buylbenzenesulfonyl chloride with the appropriate startingmaterial, the following compounds were made:

-   nonanoic acid    {1-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;    MS (ESI) 450 (MH⁺);-   4-methoxy-N-{1-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzamide;    MS (ESI) 444 (MH⁺);-   4-methoxy-N-{1-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 480 (MH⁺);-   benzo[1,3]dioxole-5-carboxylic acid    {1-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;    MS (ESI) 458 (MH⁺);-   N-{1-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methyl-terephthalamic    acid methyl ester; MS (ESI) 472 (MH⁺);-   2-methoxy-N-{1-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzamide;    MS (ESI) 444 (MH⁺);-   3-methoxy-N-{1-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzamide;    MS (ESI) 444 (MH⁺);-   N-{1-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4,N-dimethylbenzenesulfonamide;    MS (ESI) 464 (MH⁺); and-   4-cyano-N-{1-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 475 (MH⁺).

E.4-Cyano-N-{1-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide,prepared as described above in Paragraph D, was hydrolyzed withconcentrated HCl at reflux to yield4-({1-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-methyl-sulfamoyl)-benzoicacid; MS (ESI) 494 (MH⁺).

F. In a similar manner as described above in Paragraph A, but replacing3-(4-methoxyphenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one with2-(1-methylaminoethyl)-3-p-tolyl-3H-quinazolin-4-one and4-tert-butylbenzenesulfonyl chloride with the appropriate startingmaterial, the following compounds were made:

-   benzo[1,3]dioxole-5-carboxylic acid    methyl-[1-(4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]amide;    MS (ESI) 442 (MH⁺);-   4-isopropyl-N-methyl-N-[1-(4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]benzenesulfonamide;    MS (ESI) 476 (MH⁺); and-   biphenyl-4-sulfonic acid methyl-[1-(4-oxo-3-p-tolyl-3,4    dihydroquinazolin-2-yl)ethyl]amide; MS (ESI) 510 (MH⁺).

G. In a similar manner as described above in Paragraph A, but replacing3-(4-methoxyphenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one with2-aminomethyl-3-(4-methoxyphenyl)-3H-quinazolin-4-one and4-tert-butyl-benzenesulfonyl chloride with p-toluenesulfonyl chloride,the following compound was made:

-   N-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-4-methylbenzenesulfonamide;    MS (ESI) 436 (MH⁺).

H. In a similar manner as described above in Paragraph G, but replacingp-toluenesulfonyl chloride with the appropriate starting material, thefollowing compounds were made:

-   4-tert-butyl-N-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]benzenesulfonamide;    MS (ESI) 478 (MH⁺);-   N-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]benzamide;    MS (ESI) 386 (MH⁺);-   4-chloro-N-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]benzamide;    MS (ESI) 420 (MH⁺);-   3-methoxy-N-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]benzamide;    MS (ESI) 416 (MH⁺);-   4-methoxy-N-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]benzamide;    MS (ESI) 416 (MH⁺);-   4-tert-butyl-N-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]benzamide;    MS (ESI) 442 (MH⁺);-   N-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]terephthalamic    acid methyl ester; MS (ESI) 444 (MH⁺);-   2,4-dichloro-N-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]benzamide;    MS (ESI) 454 (MH⁺);-   4-methoxy-N-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]benzenesulfonamide;    MS (ESI) 452 (MH⁺);-   benzo[1,3]dioxole-5-carboxylic acid    [3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]amide;    MS (ESI) 430 (MH⁺);-   nonanoic acid    [3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]amide;    MS (ESI) 422 (MH⁺); and-   4-chloro-N-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]benzenesulfonamide;    MS (ESI) 456 (MH⁺).

I.[3-(2,4-Dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]carbamicacid benzyl ester, as prepared above in Example 4, was hydrogenated in asimilar manner as described above in Example 6, and then condensed, asdescribed above in Paragraph A, with benzenesulfonyl chloride to yieldN-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]benzenesulfonamide;MS (ESI) 420 (MH⁺).

J. In a similar manner as described above in Paragraph I, but replacingbenzenesulfonyl chloride with the appropriate starting material, thefollowing compounds were made:

-   N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-4-methylbenzenesulfonamide;    MS (ESI) 434 (MH⁺);-   4-tert-butyl-N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]benzenesulfonamide;    MS (ESI) 476 (MH⁺);-   N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-4-methoxy-benzenesulfonamide;    MS (ESI) 450 (MH⁺);-   N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]benzamide;    MS (ESI) 384 (MH⁺);-   4-tert-butyl-N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]benzamide;    MS (ESI) 440 (MH⁺);-   benzo[1,3]dioxole-5-carboxylic acid    [3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]amide;    MS (ESI) 428 (MH⁺);-   2,4-dichloro-N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]benzamide;    MS (ESI) 452 (MH⁺); and-   N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-terephthalamic    acid methyl ester; MS (ESI) 442 (MH⁺).

K. In a similar manner as described above in Paragraph A, but replacing3-(4-methoxyphenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one with3-(2,4-dimethylphenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one andreplacing 4-tert-butylbenzenesulfonyl chloride with the appropriatestarting material, the following compounds were made:

-   N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-methoxy-N-methylbenzenesulfonamide;    MS (ESI) 478 (MH⁺);-   benzo[1,3]dioxole-5-carboxylic acid    {1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;    MS (ESI) 456 (MH⁺);-   N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methyl-terephthalamic    acid methyl ester; MS (ESI) 470 (MH⁺);-   naphthalene-1-sulfonic acid {1-[3-(2,4-dimethylphenyl)-4-oxo-3,4    dihydroquinazolin-2-yl]ethyl}methylamide; MS (ESI) 498 (MH⁺);-   naphthalene-2-sulfonic acid    {1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;    MS (ESI) 498 (MH⁺);-   2-naphthalen-1-yl-ethanesulfonic acid    {1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;    MS (ESI) 526 (MH⁺);-   N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-2,N-dimethylbenzenesulfonamide;    MS (ESI) 462 (MH⁺);-   N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-3,N-dimethylbenzenesulfonamide;    MS (ESI) 462 (MH⁺);-   N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4,N-dimethylbenzenesulfonamide;    MS (ESI) 462 (MH⁺);-   N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methyl-C-phenyl-methanesulfonamide;    MS (ESI) 462 (MH⁺);-   4-acetyl-N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 490 (MH⁺);-   N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methyl-3-trifluoromethylbenzenesulfonamide;    MS (ESI) 516 (MH⁺);-   N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methyl-4-trifluoromethoxy-benzenesulfonamide;    MS (ESI) 532 (MH⁺);-   N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-2,5,N-trimethylbenzenesulfonamide;    MS (ESI) 476 (MH⁺);-   N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-3,4-dimethoxy-N-methylbenzenesulfonamide;    MS (ESI) 508 (MH⁺);-   N-[({1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methyl-sulfamoyl)-phenyl]-acetamide;    MS (ESI) 505 (MH⁺);-   N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-2,4,6,N-tetramethylbenzenesulfonamide;    MS (ESI) 490 (MH⁺);-   2-phenyl-ethenesulfonic acid    {1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;    MS (ESI) 474 (MH⁺);-   2,2,5,6,8-pentamethyl-chroman-7-sulfonic acid    {1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;    MS (ESI) 574 (MH⁺);-   thiophene-2-sulfonic acid {1-[3-(2,4-dimethylphenyl)-4-oxo-3,4    dihydroquinazolin-2-yl]ethyl}methylamide; MS (ESI) 454 (MH⁺);-   C-(7,7-dimethyl-2-oxo-bicyclo[2.2.1]hept-1-yl)-N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methyl-methanesulfonamide;    MS (ESI) 522 (MH⁺);-   N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-3,4-difluoro-N-methylbenzenesulfonamide;    MS (ESI) 484 (MH⁺);-   3-chloro-N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}2,N-dimethylbenzenesulonamide;    MS (ESI) 496 (MH⁺);-   N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-5-fluoro-2,N-dimethylbenzenesulfonamide;    MS (ESI) 480 (MH⁺);-   3,5-dimethyl-isoxazole-sulfonic acid    {1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;    MS (ESI) 467 (MH⁺);-   N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methyl-4-trifluoromethylbenzenesulfonamide;    MS (ESI) 516 (MH⁺);-   N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-3-fluoro-N-methylbenzenesulfonamide;    MS (ESI) 466 (MH⁺);-   2,4,6-trichloro-N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 550 (MH⁺);-   3-chloro-N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-fluoro-N-methylbenzenesulfonamide;    MS (ESI) 500 (MH⁺);-   2-chloro-N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 482 (MH⁺);-   5-chloro-N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-2-methoxy-N-methylbenzenesulfonamide;    MS (ESI) 512 (MH⁺);-   N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-2,5-dimethoxy-N-methylbenzenesulfonamide;    MS (ESI) 508 (MH⁺);-   N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-2,3,4-trifluoro-N-methylbenzenesulfonamide;    MS (ESI) 502 (MH⁺);-   3-chloro-N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 482 (MH⁺);-   4-cyano-N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 473 (MH⁺);-   4-butyl-N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 504 (MH⁺);-   N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-(1,1-dimethyl-propyl)-N-methylbenzenesulfonamide;    MS (ESI) 518 (MH⁺);-   4-butoxy-N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 520 (MH⁺);-   N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-3-methoxy-N-methylbenzenesulfonamide;    MS (ESI) 478 (MH⁺);-   N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-2-methoxy-4,N-dimethylbenzenesulfonamide;    MS (ESI) 492 (MH⁺);-   4-chloro-N-{1-[3-(2,4-dimethyl    phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-2,5,N-trimethylbenzenesulfonamide;    MS (ESI) 510 (MH⁺); and-   N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methyl-methanesulfonamide;    MS (ESI) 386 (MH⁺).

L. In a similar manner as described above in Paragraph A, but replacing3-(4-methoxyphenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one with3-methyl-2-(1-methylaminoethyl)-3H-quinazolin-4-one and replacing4-tert-butylbenzenesulfonyl chloride with the appropriate startingmaterial, the following compounds were made:

-   4-isopropyl-N-methyl-N-[1-(3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl]benzenesulfonamide;    MS (ESI) 400 (MH⁺);-   biphenyl-4-sulfonic acid    methyl-[1-(3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl]amide; MS    (ESI) 434 (MH⁺);-   4-methoxy-N-methyl-N-[1-(3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl]benzenesulfonamide;    MS (ESI) 388 (MH⁺); and-   4-chloro-N-methyl-N-[1-(3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl]benzenesulfonamide;    MS (ESI) 392 (MH⁺).

M. In a similar manner as described above,3-(4-methoxyphenyl)+methyl-2-(1-methylaminoethyl)-3H-quinazolin-4-one,as prepared above in Example 5, was condensed with4-tert-butylbenzenesulfonyl chloride to yield4-tert-butyl-N-{1-[3-(4-methoxyphenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;MS (ESI) 520 (MH⁺).

N. In a similar manner as described above in Paragraph M, but replacing4-tert-butylbenzenesulfonyl chloride with the appropriate startingmaterial, the following compounds were made:

-   4-isopropyl-N-{1-[3-(4-methoxyphenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 506 (MH⁺);-   biphenyl-4-sulfonic acid    {1-[3-(4-methoxyphenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;    MS (ESI) 540 (MH⁺);-   N-{1-[3-(4-methoxyphenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4,N-dimethylbenzenesulfonamide;    MS (ESI) 478 (MH⁺);-   4-methoxy-N-{1-[3-(4-methoxyphenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 494 (MH⁺);-   benzo[1,3]dioxole-5-carboxylic acid    {1-[3-(4-methoxyphenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;    MS (ESI) 472 (MH⁺);-   4-tert-butyl-N-{1-[3-(4-methoxyphenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzamide;    MS (ESI) 484 (MH⁺);-   4-butyl-N-{1-[3-(4-methoxyphenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 520 (MH⁺);-   N-{1-[3-(4-methoxyphenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}N-methyl-4-trifluoromethylbenzenesulfonamide;    MS (ESI) 532 (MH⁺); and-   2,4,6-trichloro-N-{1-[3-(4-methoxyphenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 566 (MH⁺).

O. In a similar manner as described above in Paragraph M, but replacing2-amino-3-methylbenzoic acid as an intermediate starting material in aprior step with 2-amino-6-methylbenzoic acid, the following compound wasmade:

-   4-tert-butyl-N-{1-[3-(4-methoxyphenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 520 (MH⁺).

P. In a similar manner as described above in Paragraph O, but replacing4-tert-butylbenzenesulfonyl chloride with the appropriate startingmaterial, the following compounds were made:

-   4-isopropyl-N-{1-[3-(4-methoxyphenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 506 (MH⁺);-   biphenyl-4-sulfonic acid    {1-[3-(4-methoxyphenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;    MS (ESI) 540 (MH⁺;-   N-{1-[3-(4-methoxyphenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4,N-dimethylbenzenesulfonamide;    MS (ESI) 478 (MH⁺);-   4-methoxy-N-{1-[3-(4-methoxyphenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 494 (MH⁺);-   benzo[1,3]dioxole-carboxylic acid    {1-[3-(4-methoxyphenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;    MS (ESI) 472 (MH⁺);-   4-tert-butyl-N-{1-[3-(4-methoxyphenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzamide;    MS (ESI) 484 (MH⁺);-   4-butyl-N-{1-[3-(4-methoxyphenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}N-methylbenzenesulfonamide;    MS (ESI) 520 (MH⁺);-   N-{1-[3-(4-methoxyphenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methyl-4-trifluoromethylbenzenesulfonamide;    MS (ESI) 532 (MH⁺); and-   2,4,6-trichloro-N-{1-[3-(4-methoxyphenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 566 (MH⁺).

Q. In a similar manner as described above in Paragraph M, but replacing2-amino-3-methylbenzoic acid as an intermediate starting material in aprior step with 2-amino-4-chlorobenzoic acid, the following compound wasmade:

-   4-tert-butyl-N-{1-[7-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 541 (MH⁺).

R. In a similar manner as described above in Paragraph Q, but replacing4-tert-butylbenzenesulfonyl chloride with the appropriate startingmaterial, the following compounds were made:

-   N-{1-[7-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4    isopropyl-N-methylbenzenesulfonamide; MS (ESI) 526 (MH⁺);-   biphenyl-4-sulfonic acid    {1-[7-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;    MS (ESI) 560 (MH⁺);-   N-{1-[7-chloro-3-(4-methoxyphenyl)-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-methoxy-N-methylbenzenesulfonamide;    MS (ESI) 514 (MH⁺);-   N-{1-[7-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 484 (MH⁺);-   N-{1-[7-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4,N-dimethylbenzenesulfonamide;    MS (ESI) 498 (MH⁺);-   N-{1-[7-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methyl-4-trifluoromethylbenzenesulfonamide;    MS (ESI) 552 (MH⁺);-   benzo[1,3]dioxole-5-carboxylic acid    {1-[7-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-methylamide;    MS (ESI) 492 (MH⁺); and-   4-tert-butyl-N-{1-[7-chloro-3-(4-methoxyphenyl)-4-oxo-3,4    dihydroquinazolin-2-yl]ethyl}N-methylbenzamide; MS (ESI) 504 (MH⁺).

S. In a similar manner as described above in Paragraph M, but replacing2-amino-3-methylbenzoic acid as an intermediate starting material in aprior step with the appropriate intermediate starting material, thefollowing compounds were made:

-   4-tert-butyl-N-{1-[6-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 540 (MH⁺); and-   4-tert-butyl-N-{1-[8-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 540 (MH⁺.

T. In a similar manner as described above in Paragraph S, but replacing4-tert-butylbenzenesulfonyl chloride, the following compounds were made:

-   N-{1-[6-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4    isopropyl-N-methylbenzenesulfonamide; MS (ESI) 526 (MH⁺);-   biphenyl-4-sulfonic acid    {1-[6-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;    MS (ESI) 560 (MH⁺);-   N-{1-[6-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-methoxy-N-methylbenzenesulfonamide;    MS (ESI) 514 (MH⁺);-   N-{1-[6-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 484 (MH⁺);-   N-{1-[6-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4,N-dimethylbenzenesulfonamide;    MS (ESI) 498 (MH⁺);-   N-{1-[6-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methyl-4-trifluoromethylbenzenesulfonamide;    MS (ESI) 552 (MH⁺);-   2,4,6-trichloro-N-{1-[6-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 586 (MH⁺);-   benzo[1,3]dioxole-5-carboxylic acid    {1-[6-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;    MS (ESI) 492 (MH⁺);-   4-tert-butyl-N-{1-[6-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzamide;    MS (ESI) 504 (MH⁺;-   benzo[1,3]dioxole-5-carboxylic acid    {1-[8-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;    MS (ESI) 492 (MH⁺);-   4-tert-butyl-N-{1-[8-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzamide;    MS (ESI) 504 (MH⁺);-   N-{1-[8-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-isopropyl-N-methylbenzenesulfonamide;    MS (ESI) 526 (MH⁺); and-   biphenyl-4-sulfonic acid    {1-[8-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;    MS (ESI) 560 (MH⁺).

U. In a similar manner as described above in Paragraph A,3-(4-methoxyphenyl)-7-methyl-2-(1-methylaminoethyl)-3H-quinazolin-4-one,as prepared above in Example 5, was condensed with4-tert-butylbenzenesulfonyl chloride to yield4-tert-butyl-N-{1-[3-(4-methoxyphenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;MS (ESI) 520 (MH⁺).

V. In a similar manner as described above in Paragraph U, but replacing4-tert-butylbenzenesulfonyl chloride with the appropriate startingmaterial, the following compounds were made:

-   4-isopropyl-N-{1-[3-(4-methoxyphenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 506 (MH⁺);-   biphenyl-4-sulfonic acid    {1-[3-(4-methoxyphenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;    MS (ESI) 540 (MH⁺);-   N-{1-[3-(4-methoxyphenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4,N-dimethylbenzenesulfonamide;    MS (ESI) 478 (MH⁺);-   4-methoxy-N-{1-[3-(4-methoxyphenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}N-methylbenzenesulfonamide;    MS (ESI) 494 (MH⁺);-   benzo[1,3]dioxole-5-carboxylic acid    {1-[3-(4-methoxyphenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;    MS (ESI) 472 (MH⁺);-   4-tert-butyl-N-{1-[3-(4-methoxyphenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzamide;    MS (ESI) 484 (MH⁺);-   4-butyl-N-{1-[3-(4-methoxyphenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 520 (MH⁺);-   N-{1-[3-(4-methoxyphenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methyl-4-trifluoromethylbenzenesulfonamide;    MS (ESI) 532 (MH⁺); and-   2,4,6-trichloro-N-{1-[3-(4-methoxyphenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}N-methylbenzenesulfonamide;    MS (ESI) 566 (MH⁺).

W. In a similar manner as described above in Paragraph A,8-methoxy-3-(4-methoxyphenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one,as prepared above in Example 5, was condensed with4-tert-butylbenzenesulfonyl chloride to yield4-tert-butyl-N-{1-[8-methoxy-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;MS (ESI) 536 (MH⁺).

X. In a similar manner as described above in Paragraph W, but replacing4-tert-butylbenzenesulfonyl chloride with the appropriate startingmaterial, the following compounds were made:

-   4-isopropyl-N-{1-[8-methoxy-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 522 (MH⁺);-   biphenyl-4-sulfonic acid    {1-[8-methoxy-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;    MS (ESI) 556 (MH⁺);-   benzo[1,3]dioxole-5-carboxylic acid    {1-[8-methoxy-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;    MS (ESI) 488 (MH⁺); and-   4-tert-butyl-N-{1-[8-methoxy-3-(4-methoxyphenyl)-4-oxo-3,4    dihydroquinazolin-2-yl]ethyl}-N-methylbenzamide; MS (ESI) 500 (MH⁺).

Y. In a similar manner as described above in Paragraph A,5-methoxy-3-(4-methoxyphenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one,as prepared above in Example 5, was condensed with4-tert-butylbenzenesulfonyl chloride to yield4-tert-butyl-N-{1-[5-methoxy-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;MS (ESI) 536 (MH⁺).

Z. In a similar manner as described above in Paragraph Y, but replacing4-tert-butylbenzenesulfonyl chloride with the appropriate startingmaterial, the following compounds were made:

-   4-isopropyl-N-{1-[5-methoxy-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesuionamide;    MS (ESI) 522 (MH⁺);-   biphenyl-4-sulfonic acid    {1-[5-methoxy-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;    MS (ESI) 556 (MH⁺);-   benzo[1,3]dioxole-5-carboxylic acid    {1-[5-methoxy-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;    MS (ESI) 488 (MH⁺); and-   4-tert-butyl-N-{1-[5-methoxy-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzamide;    MS (ESI) 500 (MH⁺).

AA. In a similar manner as described above in Paragraph A, but replacing3-(4-methoxyphenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one with6-methoxy-3-(4-methoxyphenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-oneand 4-tert-butylbenzenesulfonyl chloride with the appropriate startingmaterial, the following compounds were made:

-   4-isopropyl-N-{1-[6-methoxy-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 522 (MH⁺);-   biphenyl-4-sulfonic acid    {1-[6-methoxy-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;    MS (ESI) 556 (MH⁺); and-   benzo[1,3]dioxole-5-carboxylic acid    {1-[6-methoxy-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;    MS (ESI) 488 (MH⁺).

BB. In a similar manner as described above in Paragraph A, but replacingp-anisidine as an intermediate starting material in a prior step with4-tert-butylaniline, the following compound was prepared:

-   4-tert-butyl-N-{1-[3-(4-tert-butyl-phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 532 (MH⁺).

CC. In a similar manner as described above in Paragraph BB, butreplacing 4-tert-butylbenzenesulfonyl chloride with the appropriatestarting material, the following compounds were made:

-   N-{1-[3-(4-tert-butyl-phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-isopropyl-N-methylbenzenesulfonamide;    MS (ESI) 518 (MH⁺);-   biphenyl-4-sulfonic acid    {1-[3-(4-tert-butyl-phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;    MS (ESI) 552 (MH⁺);-   4-tert-butyl-N-{1-[3-(4-tert-butyl-phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzamide;    MS (ESI) 496 (MH⁺); and-   benzo[1,3]dioxole-5-carboxylic acid    {1-[3-(4-tert-butyl-phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;    MS (ESI) 484 (MH⁺).

DD. In a similar manner as described above in Paragraph A, but replacingp-anisidine as an intermediate starting material in a prior step withm-anisidine, the following compound was prepared:

-   4-tert-butyl-N-{1-[3-(3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 506 (MH⁺).

EE. In a similar manner as described above in Paragraph DD, butreplacing 4-tert-butylbenzenesulfonyl chloride with the appropriatestarting material, the following compounds were made:

-   4-isopropyl-N-{1-[3-(3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 492 (MH⁺);-   biphenyl-4-sulfonic acid    {1-[3-(3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;    MS (ESI) 526 (MH⁺);-   4-tert-butyl-N-{1-[3-(3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzamide;    MS (ESI) 470 (MH⁺); and-   benzo[1,3]dioxole-5-carboxylic acid    {1-[3-(3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;    MS (ESI) 458 (MH⁺).

FF. In a similar manner as described above in Paragraph A, but replacingp-anisidine as an intermediate starting material in a prior step witho-anisidine, the following compound was prepared:

-   4-tert-butyl-N-{1-[3-(2-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 506 (MH⁺).

GG. In a similar manner as described above in Paragraph FF, butreplacing 4-tert-butylbenzenesulfonyl chloride with the appropriatestarting material, the following compounds were made:

-   4-isopropyl-N-{1-[3-(2-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 492 (MH⁺);-   biphenyl-4-sulfonic acid    {1-[3-(2-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;    MS (ESI) 526 (MH⁺);-   4-tert-butyl-N-{1-[3-(2-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzamide;    MS (ESI) 470 (MH⁺); and-   benzo[1,3]dioxole-5-carboxylic acid    {1-[3-(2-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;    MS (ESI) 458 (MH⁺).

HH. In a similar manner as described above in Paragraph A, but replacingp-anisidine as an intermediate starting material in a prior step with4-trifluoromethoxyaniline, the following compound was prepared:

-   4-tert-butyl-N-methyl-N-{1-[4-oxo-3-(4-trifluoromethoxyphenyl)-3,4-dihydroquinazolin-2-yl]ethyl}benzenesulfonamide;    MS (ESI) 560 (MH⁺).

II. In a similar manner as described above in Paragraph HH, butreplacing 4-tert-butylbenzenesulfonyl chloride with the appropriatestarting material, the following compounds were made:

-   4-isopropyl-N-methyl-N-{1-[4-oxo-3-(4-trifluoromethoxyphenyl)-3,4-dihydroquinazolin-2-yl]ethyl}benzenesulfonamide;    MS (ESI) 546 (MH⁺);-   biphenyl-4-sulfonic acid    methyl-{1-[4-oxo-3-(4-trifluoromethoxyphenyl)-3,4-dihydroquinazolin-2-yl]ethyl}amide;    MS (ESI) 580 (MH⁺);-   4-tert-butyl-N-methyl-N-{1-[4-oxo-3-(4-trifluoromethoxyphenyl)-3,4-dihydroquinazolin-2-yl]ethyl}benzamide;    MS (ESI) 524 (MH⁺); and-   benzo[1,3]dioxole-5-carboxylic acid    methyl-{1-[4-oxo-3-(4-trifluoromethoxyphenyl)-3,4-dihydroquinazolin-2-yl]ethyl}amide;    MS (ESI) 512 (MH⁺).

JJ. In a similar manner as described above in Paragraph A, but replacingp-anisidine as an intermediate starting material in a prior step with 4trifluoromethylaniline, the following compound was prepared:

-   4-tert-butyl-N-methyl-N-{1-[4-oxo-3-(4-trifluoromethylphenyl)-3,4-dihydroquinazolin-2-yl]ethyl}-benzenesulfonamide;    MS (ESI) 544 (MH⁺).

KK. In a similar manner as described above in Paragraph JJ, butreplacing 4-tert-butylbenzenesulfonyl chloride with the appropriatestarting material, the following compounds were made:

-   4-isopropyl-N-methyl-N-{1-[4-oxo-3-(4-trifluoromethylphenyl)-3,4-dihydroquinazolin-2-yl]ethyl}-benzenesulfonamide;    MS (ESI) 530 (MH⁺);-   biphenyl-4-sulfonic acid    methyl-{1-[4-oxo-3-(4-trifluoromethylphenyl)-3,4-dihydroquinazolin-2-yl]ethyl}-amide;    MS (ESI) 564 (MH⁺);-   benzo[1,3]dioxole-5-carboxylic acid    methyl-{1-[4-oxo-3-(4-trifluoromethylphenyl)-3,4-dihydroquinazolin-2-yl]ethyl}-amide;    MS (ESI) 496 (MH⁺); and-   4-tert-butyl-N-methyl-N-{1-[4-oxo-3-(4-trifluoromethylphenyl)-3,4-dihydroquinazolin-2-yl]ethyl}-benzamide;    MS (ESI) 508 (MH⁺).

Example 8 Preparation of4-tert-butyl-N-{1-[3-(4-methoxyphenyl)-4-oxo-3,4-Dihydroquinazolin-2-yl]ethyl}-N-methylbenzamideand Related Compounds

A. To a suspension of the3-(4-methoxyphenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one (50 mg,0.16 mmol) stirring in 2 mL DCM was added TEA (19 mg, 0.19 mmol)followed by the addition of neat 4-tert-butylbenzoyl chloride (31 mg,0.16 mmol). The reaction was allowed to stir at room temperature for 2 hthen treated with tris-amine (100 mg). The reaction was allowed to standfor 15 min at room temperature after which the resin was removed byfiltration. The filtrate was concentrated under vacuum to afford thecrude product. The crude residue was purified by flash chromatography(silica gel, 50% EtOAc/Hex) to afford the desired product as an offwhite powder (73 mg, 97% yield). ¹H-NMR (CDCl₃): δ 8.15 (d, 1H), 7.55(m, 1H), 7.39 (m, 4H), 7.25 (d, 1H), 7.16 (m, 2H), 7.09 (m, 1H), 6.70(m, 2H), 4.90 (q, 1H), 4.83 (s, 3H), 3.11 (s, 3H) 1.22 (d, 3H), 1.09 (s,9H); MS (ESI) 470 (MH⁺).

B. In a similar manner, but replacing 4-tert-butylbenzoyl chloride withoctanoyl chloride and3-(4-methoxyphenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one with3-(2,4-dimethylphenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one, thefollowing compound was made:

nonanoic acid{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;¹H-NMR (CDCl₃): δ 8.32 (m, 1H), 7.80 (m, 2H), 7.55 (m, 1H), 7.19 (m,2H), 7.06 (m, 1H), 5.44 (q, 1H), 2.92 (m, 3H), 2.39 (m, 3H), 2.25 (m,2H), 2.03 (m, 3H), 1.47 (m, 5H), 1.29 (m, 10H), 0.9 (m, 3H); MS (ESI)448 (MH⁺).

C. In a similar as described above in Paragraph A, but replacing3-(4-methoxyphenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one with theappropriate starting material, the following compounds were made:

4-tert-butyl-N-{1-[3-(4-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]methyl}-N-methylbenzamide;¹H-NMR (CDCl₃): δ 8.31 (d, 1H), 7.80 (t, 1H), 7.73 (m, 1H), 7.64 (m,1H), 7.52 (t, 1H), 7.42 (m, 2H), 7.29 (m, 5H), 5.8 (q, 1H), 3.15 (s,3H), 1.53 (d, 3H), 1.34 (s, 9H); MS (ESI) 458 (MH⁺);

4-tert-butyl-N-{1-[6-methoxy-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzamide;¹H-NMR (CDCl₃): δ 7.63 (m, 2H), 7.48 (m, 1H), 7.37 (m, 3H), 7.28 (m,2H), 7.21 (m, 1H), 7.04 (m, 2H), 5.46 (q, 1H), 3.91 (s, 3H), 3.83 (s,3H), 1.48 (d, 3H), 1.31 (s, 9H); MS (ESI) 500 (MH⁺);

4-tert-butyl-N-{1-[3-(4-methoxyphenyl)-6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzamide;¹H-NMR (CDCl₃): δ 8.06 (m, 1H), 7.59 (m, 2H), 7.49 (m, 1H), 7.38 (m,2H), 7.28 (m, 2H), 7.21 (m, 1H), 7.04 (m, 2H), 5.45 (q, 1H), 3.83 (s,3H), 3.08 (s, 3H), 2.49 (s, 3H), 1.48 (d, 3H), 1.31 (s, 9H); MS (ESI)484 (MH⁺); and

4-tert-butyl-N-methyl-N-[1-(3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl]benzamide;¹H-NMR (CDCl₃): δ 8.65 (d, 1H), 7.59 (broad, 1H), 7.44 (m, 5H), 7.08 (t,1H), 6.22 (q, 1H), 3.02 (s, 3H), 3.01 (s, 3H), 1.54 (d, 3H), 1.33 (s,9H); MS (ESI) 378 (MH⁺).

D. In a similar manner as described above in Paragraph A, but replacing3-(4-methoxyphenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one with3-(4-fluorophenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one and4-tert-butylbenzoyl chloride with the appropriate starting material, thefollowing compounds were made:

-   4-tert-butyl-N-{1-[3-(4-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 494 (MH⁺);-   N-{1-[3-(4-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-isopropyl-N-methylbenzenesulfonamide;    MS (ESI) 480 (MH⁺); and-   biphenyl-4-sulfonic acid    {1-[3-(4-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;    MS (ESI) 514 (MH⁺).

E. In a similar manner, but replacing3-(4-methoxyphenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one with3-(4-methoxyphenyl)-6-methyl-2-(1-methylaminoethyl)-3H-quinazolin-4-oneand replacing 4-tert-butylbenzoyl chloride with the appropriate startingmaterial, the following compounds were made:

-   4-tert-butyl-N-{1-[3-(4-methoxyphenyl)-6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 520 (MH⁺);-   4-isopropyl-N-{1-[3-(4-methoxyphenyl)-6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 506 (MH⁺);-   biphenyl-4-sulfonic acid    {1-[3-(4-methoxyphenyl)-6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;    MS (ESI) 540 (MH⁺);-   N-{1-[3-(4-methoxyphenyl)-6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4,N-dimethylbenzenesulfonamide;    MS (ESI) 478 (MH⁺);-   4-methoxy-N-{1-[3-(4-methoxyphenyl)-6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 494 (MH⁺);-   benzo[1,3]dioxole-5-carboxylic acid    {1-[3-(4-methoxyphenyl)-6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-methylamide;    MS (ESI) 472 (MH⁺);-   4-butyl-N-{1-[3-(4-methoxyphenyl)-6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 520 (MH⁺);-   N-{1-[3-(4-methoxyphenyl)-6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methyl-4-trifluoromethylbenzenesulfonamide;    MS (ESI) 532 (MH⁺); and-   2,4,6-trichloro-N-{1-[3-(4-methoxyphenyl)-6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 566 (MH⁺).

Example 9 Preparation ofn-[1-(3-biphenyl-4-yl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl]-4-tert-butyl-n-methylbenzenesulfonamideand related Compounds

A. An oven-dried flask charged withN-{1-[3-(4-bromophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-tert-butyl-N-methylbenzenesulfonamide(103 mg, 0.19 mmol) was diluted with 2 mL of a nitrogen-purged solutionof DME/H₂O (1:1). The resulting reaction mixture was then treated withK₂CO₃ (78.8 mg, 0.57 mmol) and phenyl boronic acid (46.3 mg, 0.38 mmol)at room temperature under a nitrogen atmosphere. In a separate ovendried vial containing triphenyl phosphine (43.9 mg, 0.17 mmol) and Pd₂dba₃:CHCl₃ (17 mg, 0.019 mmol) was placed 1 mL of the nitrogen purgedDMFE/H₂O solution (1:1). The contents of the vial were stirred until thePd(0) was completely dissolved. The premixed palladium solution was thenadded to the reaction mixture and heated to 70° C. under nitrogen for 16h. The reaction mixture was cooled to room temperature and concentratedunder vacuum. The resulting residue was then taken up in EtOAc andfiltered through a plug of silica. The filtrate was concentrated undervacuum to afford a crude residue that was purified by chromatography(silica gel, 0-75% EtOAC:Hex) to afford the desired product as a whitesolid (74 mg, 71% yield). ¹H-NMR (CDCl₃): δ 8.26 (d, 1H), 7.88 (d, 1H),7.76 (d, 1H), 7.67 (m, 4H), 7.45 (m, 7H), 7.23 (m, 3H), 4.99 (q, 1H),3.20 (s, 3H), 1.33 (d, 3H), 1.16 (s, 9H); MS (ESI) 552 (MH⁺).

B. In a similar manner, but replacing phenyl boronic acid with theappropriate starting material, the following compounds were made:

4-tert-butyl-N-methyl-N-{1-[4-oxo-3-(4-thiophen-2-ylphenyl)-3,4-dihydroquinazolin-2-yl]ethyl}benzenesulfonamide;¹H-NMR (CDCl₃): δ 8.23 (m, 1H), 7.79 (m, 1H), 7.67 (m, 3H), 7.47 (m,7H), 7.39 (m, 2H), 7.08 (m, 1H), 4.90 (q, 1H), 3.12 (s, 3H), 3.12 (s,3H), 1.29 (d, 3H), 1.20 (s, 9H); MS (ESI) 558 (MH⁺);

4-tert-butyl-N-{1-[3-(3′-methoxy-biphenyl-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;¹H-NMR (CDCl₃): δ 8.25 (d, 1H), 7.87 (m, 1H), 7.75 (m, 1H), 7.65 (m,2h), 7.52 (m, 2H), 7.41 (m, 3H), 7.25 (m, 5H), 6.95 (m, 1H), 4.98 (q,1H), 3.89 (s, 3H), 3.20 (s, 3H), 1.31 (d, 3H), 1.16 (s, 9H); MS (ESI)582 (MH⁺);

4-tert-butyl-N-{1-[3-(3′-chloro-biphenyl-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;¹H-NMR (CDCl₃): δ 8.25 (d, 1H), 7.86 (m, 1H), 7.73 (m, 1H), 7.66 (m,3H), 7.55 (m, 1H), 7.52 (d, 2H), 7.46 (t, 1H), 7.40 (m, 3H), 7.26 (m,3H), 4.97 (q, 1H), 3.16 (d, 3H), 1.31 (d, 3H), 1.17 (s, 9H); MS (ESI)587 (MH⁺);

-   4-tert-butyl-N-methyl-N-{1-[3-(2′-methyl-biphenyl-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-benzenesulfonamide;    MS (ESI) 566 (MH⁺);-   4-tert-butyl-N-methyl-N-{1-[3-(3′-methyl-biphenyl-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-benzenesulfonamide;    MS (ESI) 566 (MH⁺);-   4-tert-butyl-N-methyl-N-{1-[3-(4′-methyl-biphenyl-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-benzenesulfonamide;    MS (ESI) 566 (MH⁺);-   4-tert-butyl-N-{1-[3-(2′-chloro-biphenyl-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 586 (MH⁺);-   4-tert-butyl-N-{1-[3-(4′-chloro-biphenyl-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 586 (MH⁺);-   4-tert-butyl-N-{1-[3-(2′-methoxy-biphenyl-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 582 (MH⁺);-   4-tert-butyl-N-{1-[3-(4′-methoxy-biphenyl-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 582 (MH⁺);-   4′-(2-{1-[(4-tert-butylbenzenesulfonyl)methylamino]ethyl}-4-oxo-4H-quinazolin-3-yl)-biphenyl-4-carboxylic    acid; MS (ESI) 596 (MH⁺);-   4-tert-butyl-N-{1-[3-(4′-cyano-biphenyl-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 577 (MH⁺);-   4-tert-butyl-N-methyl-N-{1-[4-oxo-3-(4-thiophen-3-ylphenyl)-3,4-dihydroquinazolin-2-yl]ethyl}-benzenesulfonamide;    MS (ESI) 558 (MH⁺);-   4′-(2-{1-[(4-tert-butylbenzenesulfonyl)methylamino]ethyl}-4-oxo-4H-quinazolin-3-yl)-biphenyl-3-carboxylic    acid methyl ester; MS (ESI) 610 (MH⁺);-   4′-(2-{1-[(4-tert-butylbenzenesulfonyl)methylamino]ethyl}-4-oxo-4H-quinazolin-3-yl)-biphenyl-4-carboxylic    acid methyl ester; MS (ESI) 610 (MH⁺);-   4′-(2-{1-[(4-tert-butylbenzenesulfonyl)-methylamino]ethyl}-4-oxo-4H-quinazolin-3-yl)-biphenyl-3-carboxylic    acid; MS (ESI) 596 (MH⁺); and

C. The following three compounds were made by a modification of theprocedure in paragraph B, as described in Wolfe et al., J. Org. Chem.(2000), Vol. 65, pp. 1158-1174.

4-tert-butyl-N-methyl-N-{1-[4-oxo-3-(4-piperidin-1-yl-phenyl)-3,4-dihydroquinazolin-2-yl]ethyl}benzenesulfonamide;¹H-NMR (CDCl₃): δ 8.21 (m, 11H), 7.60 (m, 2H), 7.51 (d, 2H), 7.39 (m,2H), 7.20 (m, 2H), 7.13 (m, 1H), 7.00 (m, 2H), 5.01 (q, 11H), 3.29 (m,4H), 3.23 (s, 3H), 1.74 (m, 4H), 1.30 (d, 3H), 1.26 (m, 2H), 1.14 (s,9H); MS (ESI) 559 (MH⁺);

-   4-tert-butyl-N-methyl-N-{1-[4-oxo-3-(4-pyrrolidin-1-ylphenyl)-3,4-dihydroquinazolin-2-yl]ethyl}benzenesulfonamide;    MS (ESI) 545 (MH⁺); and

4-tert-butyl-N-methyl-N-{1-[3-(4-morpholin-4-ylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}benzenesulfonamide;¹H-NMR (CDCl₃): δ 8.22 (d, 1H), 7.62 (m, 11H), 7.52 (d, 2H), 7.424 (m,2H), 7.30 (d, 11H), t.22 (d, 2H), 7.14 (d, 11H), 7.03 (m, 2H), 5.01 (q,11H), 3.90 (s, 3H), 3.28 (m, 3H), 3.21 (s, 3H), 1.31 (d, 3H), 1.14 (s,9H); MS (ESI) 561 (MH⁺.

D. In a similar manner as described above in Paragraph A, but replacingphenyl boronic acid with thiophene-2-boronic acid andN-{1-[3-(4-bromophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-tert-butyl-N-methylbenzenesulfonamidewithN-[1-(6-bromo-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]-4-tert-butyl-N-methylbenzenesulfonamide,the following compound was made:

4-tert-butyl-N-{1-[3-(4-methoxyphenyl)-4-oxo-6-thiophen-2-yl-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;¹H-NMR (CDCl₃): δ 8.34 (d, 1H), 7.71 (m, 2H), 7.5 (d, 2H), 7.46 (m, 3H),7.35 (d, 1H), 7.22 (m, 4H) 7.05 (d, 1H), 4.92 (q, 1H), 3.17 (s, 3H),2.48 (s, 3H), 1.29 (d, 3H), 1.19 (s, 9H); MS (ESI) 570 (MH⁺).

E. In a similar manner as described above in Paragraph D, but replacingthiophene-2-boronic acid with the appropriate starting material, thefollowing compounds were made:

4-[2-{1-[(4-tert-butyl-benzenesulfonyl)methylamino]ethyl}-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl]benzoicacid; ¹H-NMR (CDCl₃): δ 8.48 (d, 1H), 8.21 (m, 2H), 7.92 (m, 1H), 7.74(d, 2H), 7.54 (d, 2H), 7.46 (m, 4H), 7.36 (m, 1H), 7.24 (m, 1H), 7.08(m, 1H), 4.96 (q, 1H), 3.21 (s, 3H), 2.49 (s, 3H), 1.32 (d, 3H), 1.15(s, 9H); MS (ESI) 610 (MH⁺);

4-tert-butyl-N-{1-[3-(4-methoxyphenyl)-4-oxo-6-m-tolyl-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;¹H-NMR (CDCl₃): δ 8.41 (m, 1H), 7.87 (m, 2H), 7.53 (m, 2H), 7.45 (m,3H), 7.37 (m, 3H), 7.23 (m, 3H), 7.07 (m, 1H), 4.96 (q, 1H), 3.21 (s,3H), 2.49 (s, 3H), 2.43 (s, 3H), 1.32 (d, 3H), 1.15 (s, 9H); MS (ESI)580 (MH⁺);

4-tert-butyl-N-{1-[6-(3-chlorophenyl)-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;¹H-NMR (CDCl₃): δ 8.39 (d, 1H), 7.84 (m, 1H), 7.61 (m, 1H), 7.53 (m,2H), 7.47 (m, 3H), 7.40 (d, 2H), 7.37 (m, 2H), 7.24 (m, 2H), 7.07 (m,1H), 4.95 (q, 1H), 3.20 (s, 3H), 2.49 (s, 3H), 1.31 (d, 3H), 1.15 (s,9H); MS (ESI) 601 (MH⁺);

4-tert-butyl-N-{1-[3-(4-methoxyphenyl)-4-oxo-6-thiophen-3-yl-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;¹H-NMR (CDCl₃): δ 8.33 (d, 1H), 7.71 (m, 1H), 7.50 (m, 3H), 7.44 (m,3H), 7.35 (m, 1H), 7.22 (m, 4H), 7.04 (m, 1H), 4.91 (q, 1H), 3.17 (s,3H), 2.48 (s, 3H), 1.29 (d, 3H), 1.17 (s, 9H); MS (ESI) 570 (MH⁺);

-   4-tert-butyl-N-methyl-N-[1-(4-oxo-6-phenyl-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]benzenesulfonamide;    MS (ESI) 566 (MH⁺);-   4-tert-butyl-N-methyl-N-[1-(4-oxo-6-o-tolyl-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]benzenesulfonamide;    MS (ESI) 580 (MH⁺);-   4-tert-butyl-N-methyl-N-[1-(4-oxo-3,6-di-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]benzenesulfonamide;    MS (ESI) 580 (MH⁺);-   4-tert-butyl-N-{1-[6-(2-chlorophenyl)-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 600 (MH⁺);-   4-tert-butyl-N-{1-[6-(4-chlorophenyl)-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 600 (MH⁺);-   4-tert-butyl-N-{1-[6-(2-methoxyphenyl)-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 596 (MH⁺);-   4-tert-butyl-N-{1-[6-(3-methoxyphenyl)-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 596 (MH⁺);-   4-tert-butyl-N-{1-[6-(4-methoxyphenyl)-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 596 (MH⁺);-   3-(2-{1-[(4-tert-butyl-benzenesulfonyl)methylamino]ethyl}-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-6-yl)benzoic    acid methyl ester; MS (ESI) 624 (MH⁺);-   4-(2-{1-[(4-tert-butyl-benzenesulfonyl)methylamino]ethyl}-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-6-yl)-benzoic    acid methyl ester; MS (ESI) 624 (MH⁺);-   3-(2-{1-[(4-tert-butylbenzenesulfonyl)methylamino]ethyl}-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-6-yl)benzoic    acid; MS (ESI) 610 (MH⁺); and-   4-tert-butyl-N-{1-[6-(4-cyanophenyl)-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 591 (MH⁺).

F. The following three compounds were made by a modification of theprocedure in paragraph D, as described in Wolfe et al., J. Org. Chem.(2000), Vol. 65, pp. 1158-1174.

4-tert-butyl-N-{1-[3-(4-methoxyphenyl)-4-oxo-6-pyrrolidin-1-yl-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;¹H-NMR (CDCl₃): δ 7.51 (d, 2H), 7.43 (m, 2H), 7.33 (d, 1H), 7.24 (m,3H), 7.17 (m, 1H), 7.05 (d, 1H), 6.93 (d, 1H), 4.92 (q, 1H), 3.35 (m,4H), 3.12 (s, 3H), 2.47 (s, 3H), 2.04 (m, 4H), 1.28 (d, 3H), 1.18 (s,9H); MS (ESI) 559 (MH⁺);

-   4-tert-butyl-N-methyl-N-[1-(6-morpholin-4-yl-4-oxo-3-p-tolyl-3,4    dihydroquinazolin-2-yl)ethyl]benzenesulfonamide; MS (ESI) 575 (MH⁺);    and-   4-tert-butyl-N-methyl-N-[1-(4-oxo-6-piperidin-1-yl-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]benzenesulfonamide;    MS (ESI) 573 (MH⁺).

Example 10 Preparation of4-tert-butyl-N-{1-[3-(4-hydroxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamideand related Compounds

A. To a suspension of the4-tert-butyl-N-{1-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide(0.5 g, 1.07 mmol) stirring in 15 mL DCM was added boron tribromide (5mL, 5 mmol 1 M in DCM). The reaction was allowed to stir at roomtemperature for 15 min after which TLC analysis indicated that startingmaterial was completely consumed. The reaction was quenched with 20 mLbrine and the resulting mixture was transferred to a separatory funnel.The layers were separated and the aqueous layer extracted with CHCl₃(2×25 mL). The combined organics were washed with brine, dried overMgSO₄, and concentrated under vacuum to afford a crude residue that waspurified by chromatography (silica gel, 0-75% EtOAc:Hex), yielding thedesired product as a white solid (0.735 g, 95%). ¹H-NMR (CDCl₃): δ 8.26(d, 1H), 7.67 (t, 1H), 7.51 (d, 2H), 7.45 (t, 1H), 7.36 (m, 2H), 7.26(d, 2H), 6.98 (m, 1H), 6.90 (m, 2H), 5.00 (q, 1H), 3.19 (s, 3H), 1.28(d, 3H), 1.17 (s, 9H); MS (ESI) 492 (MH⁺).

B. In a similar manner, but replacing 4-tert-butyl-N-{1-[3-(4methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamidewith4-tert-butyl-N-[1-(6-methoxy-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]-N-methylbenzenesulfonamide,the following compound was made:

4-tert-butyl-N-[1-(6-hydroxy-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]-N-methylbenzenesulfonamide;¹H-NMR (CDCl₃): δ 7.82 (d, 1H), 7.49 (m, 3H), 7.42 (d, 1H), 7.36 (d,1H), 7.24 (m, 4H), 7.06 (d, 1H), 6.21 (s, 1H), 4.94 (q, 1H), 3.13 (s,3H), 2.48 (s, 3H), 1.27 (d, 3H), 1.18 (s, 9H); MS (ESI) 506 (MH⁺).

C. In a similar manner described above in Paragraph A,4-tert-butyl-N-{1-[5-hydroxy-3-(4-hydroxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;MS (ESI) 508 (MH⁺); was prepared from4-tert-butyl-N-{1-[5-methoxy-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide,which was prepared as described above in Example 7.

Example 11 Preparation ofN-{1-[3-(4-benzyloxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-tert-butyl-N-methylbenzenesulfonamideand Related Compounds

A. To a solution of4-tert-butyl-N-{1-[3-(4-hydroxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide(50 mg, 0.11 mmol) in anhydrous THF (2 mL) were added triphenylphosphine(0.115 mg, 0.44 mmol), diisopropyl azodicarboxylate (88.9 mg, 0.44mmol), and benzyl alcohol (48.5 mg, 0.44 mmol) at 0° C. The mixture wasstirred for 1 h at this temperature and then allowed to warm to roomtemperature and stirred overnight. The solvent was evaporated underreduced pressure, and the crude residue was purified by chromatography(silica gel, 0-50% EtOAc:Hex) to yield the desired product as a whitesolid (48 mg, 80%). ¹H-NMR (CDCl₃): δ 8.22 (d, 1H), 7.64 (m, 1H), 7.49(m, 5H), 7.42 (m, 3H), 7.34 (m, 2H), 7.24 (m, 3H), 7.10 (m, 2H), 5.15(s, 2H), 4.99 (q, 1H), 3.19 (s, 3H), 1.30 (d, 3H), 1.16 (s, 9H); MS(ESI) 582 (MH⁺).

B. In a similar manner, but replacing benzyl alcohol with theappropriate starting material, the following compounds were made:

4-tert-butyl-N-{1-[3-(4-ethoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;¹H-NMR (CDCl₃): δ 8.22 (d, 1H), 7.64 (t, 1H), 7.43 (m, 2H), 7.33 (d,1H), 7.23 (m, 2H), 7.15 (d, 1H), 7:05 (dd, 2H), 4.98 (q, 1H), 4.13 (q,2H), 3.19 (s, 3H), 1.47 (t, 3H), 1.29 (d, 3H), 1.16 (s, 9H); MS (ESI)520 (MH⁺);

4-tert-butyl-N-methyl-N-(1-{4-oxo-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-3,4-dihydroquinazolin-2-yl}ethyl)benzenesulfonamide;¹H-NMR (CDCl₃): δ 8.23 (d, 1H), 7.67 (m, 2H), 7.46 (m, 4H), 7.30 (d,2H), 7.15 (m, 2H), 7.06 (m, 1H), 5.00 (q, 1H), 4.50 (m, 2H), 3.76 (m,2H), 3.54 (m, 2H), 3.07 (s, 3H), 1.28 (d, 3H), 1.17 (s, 9H); MS (ESI)603 (MH⁺);

4-tert-butyl-N-methyl-N-(1-{3-[4-(2-morpholin-4-yl-ethoxy)phenyl]-4-oxo-3,4-dihydroquinazolin-2-yl}ethyl)benzenesulfonamide;¹H-NMR (CDCl₃): δ 8.25 (d, 1H), 7.69 (t, 1H), 7.53 (d, 2H), 7.46 (m,3H), 7.31 (d, 2H), 7.15 (m, 2H), 7.07 (m, 1H), 5.00 (q, 1H), 4.52 (m,2H), 4.01 (m, 4H) 3.71 (m, 2H), 3.58 (m, 2H), 3.09 (m, 2H), 3.03 (m,2H), 2.72 (s, 3H), 1.28 (d, 3H), 1.21 (s, 9H); MS (ESI) 605 (MH⁺);

[4-(2-{1-[(4-tert-butylbenzenesulfonyl)methylamino]ethyl}4-oxo-4H-quinazolin-3-yl)phenoxy]aceticacid ethyl ester; ¹H-NMR (CDCl₃): δ 8.22 (d, 1H, 7.65 (t, 1H), 7.50 (d,3H), 7.44 (t, 1H), 7.36 (d, 1H), 7.27 (s, 2H), 7.16 (d, 1H), 7.10 (s,2H), 4.94 (q, 1H), 4.71 (s, 2H), 4.31 (q, 2H), 3.17 (s, 3H), 1.33 (t,3H), 1.26 (d, 2H), 1.18 (s, 9H); MS (ESI) 578 (MH⁺);

4-tert-butyl-N-(1-{3-[4-(2-methoxyethoxy)phenyl]-4-oxo-3,4-dihydroquinazolin-2-yl}ethyl)-N-methylbenzenesulfonamide;¹H-NMR (CDCl₃): δ 8.22 (d, 1H), 7.64 (t, 1H), 7.45 (m, 4H), 7.33 (d, 1h), 7.21 (m, 3H), 7.09 (s, 2H), 4.97 (q, 1H), 4.22 (t, 2H), 3.81 (t,2H), 3.49 (s, 3H), 3.19 (d, 3H), 1.28 (d, 3H), 1.17 (s, 9H); MS (ESI)550 (MH⁺);

-   4-tert-butyl-N-{1-[3-(4-n-butoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-methylbenzenesulfonamide;-   4-tert-butyl-N-{1-[3-(4-isopropoxy-phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 534 (MH⁺); and-   4-tert-butyl-N-{1-[3-(4-isobutoxy-phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 548 (MH⁺).

C. In a similar manner as described above in Paragraph A, but replacing4-tert-butyl-N-{1-[3-(4-hydroxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamidewith4-tert-butyl-N-[1-(6-hydroxy-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]-N-methylbenzenesulfonamide,the following compounds was made:

N-[1-(6-benzyloxy-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]-4-tert-butyl-N-methylbenzenesulfonamide;¹H-NMR (CDCl₃): δ 7.67 (d, 1H), 7.50 (m, 2H), 7.44 (m, 4H), 7.39 (m,2H), 7.34 (m, 2H), 7.30 (m, 2H), 7.24 (m, 1H), 7.05 (m, 1H), 5.13 (s,2H), 4.93 (q, 1H), 3.14 (s, 3H), 2.48 (s, 3H), 1.28 (d, 3H), 1.18 (s,9H); MS (ESI) 596 (MH⁺).

D. In a similar manner as described above in Paragraph C, but replacingbenzyl alcohol with the appropriate starting material, the followingcompounds were made:

4-tert-butyl-N-[1-(6-isobutoxy-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]-N-methylbenzenesulfonamide;¹H-NMR (CDCl₃): δ 7.54 (d, 1H), 7.50 (m, 2H), 7.45 (m, 1H), 7.43 (m,1H), 7.33 (m, 1H), 7.24 (m, 4H), 7.04 (m, 1H), 4.93 (q, 1H), 3.79 (d,2H), 3.15 (s, 3H), 2.48 (s, 3H), 1.28 (d, 3H), 1.17 (s, 9H); MS (ESI)562 (MH⁺);

N-[1-(6-butoxy-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]-4-tert-butyl-N-methylbenzenesulfonamide;¹H-NMR (CDCl₃): δ 7.5 (m, 3H), 7.46 (m, 1H), 7.40 (m, 1H), 7.34 (m, 3H),7.26 (m, 2H), 7.05 (m, 1H), 4.94 (q, 1H), 4.69 (s, 2H), 4.27 (q, 2H),3.13 (s, 3H), 2.48 (s, 3H), 1.31 (t, 3H), 1.27 (d, 3H), 1.19 (s, 9H); MS(ESI) 562 (MH⁺);

(2-{1-[(4-tert-butylbenzenesulfonyl)methylamino]ethyl}-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-6-yloxy)aceticacid ethyl ester; ¹H-NMR (CDCl₃): δ 7.56 (d, 1H), 7.50 (m, 2H), 7.44 (m,2H), 7.33 (m, 1H), 7.24 (m, 4H), 7.05 (m, 1H), 4.93 (q, 1H), 4.03 (t,2H), 3.15 (s, 3H), 2.48 (s, 3H), 1.79 (m, 2H), 1.5 (m, 2H), 1.28 (d,1H), 1.18 (s, 9H), 0.98 (t, 3H); MS (ESI) 592 (MH⁺);

-   4-tert-butyl-N-[1-(6-ethoxy-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]-N-methylbenzenesulfonamide;    MS (ESI) 534 (MH⁺); and-   4-tert-butyl-N-[1-(6-isopropoxy-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]-N-methylbenzenesulfonamide;    MS (ESI) 548 (MH⁺).

E. In a similar manner as described in Paragraph A, but replacing theintermediate starting material, 4-tert-butylbenzenesulfonyl chloride, ina prior step, with an appropriate intermediate starting material, thefollowing compounds were made:

-   N-{1-[3-(4-benzyloxy-phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-isopropyl-N-methylbenzenesulfonamide;    MS (ESI) 568 (MH⁺);-   biphenyl-4-sulfonic acid    {1-[3-(4-benzyloxy-phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;    MS (ESI) 602 (MH⁺);-   benzo[1,3]dioxole-5-carboxylic acid    {1-[3-(4-benzyloxy-phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;    MS (ESI) 534 (MH⁺); and-   N-{1-[3-(4-benzyloxy-phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-tert-butyl-N-methylbenzamide;    MS (ESI) 546 (MH⁺).

Example 12 Preparation of3-(4-bromophenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one and RelatedCompounds

A. The title compound was prepared from3-(4-bromophenyl)-2-(1-chloroethyl)-3H-quinazolin-4-one (as preparedabove in Example 3) and methylamine under conditions similar to thosedescribed in Example 5 above, MS (ESI) 358 (MH⁺).

B. In a similar manner as described above in Example7,3-(4-bromophenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one wascondensed with benzylsulfonyl chloride to yieldN-{1-[3-(4-bromophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}N-methylbenzenesulfonamide;MS (ESI) 498 (MH⁺).

C. In a similar manner as described above in Paragraph B, but replacingbenzylsulfonyl chloride with the appropriate starting material, thefollowing compounds were prepared:

-   N-{1-[3-(4-bromophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-methoxy-N-methylbenzenesulfonamide;    MS (ESI) 528 (MH⁺);-   N-{1-[3-(4-bromophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4,N-dimethylbenzenesulfonamide;    MS (ESI) 512 (MH⁺);-   N-{1-[3-(4-bromophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-chloro-N-methylbenzenesulfonamide;    MS (ESI) 533 (MH⁺);-   N-{1-[3-(4-bromophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-tert-butyl-N-methylbenzenesulfonamide;    MS (ESI) 554 (MH⁺);-   N-{1-[3-(4-bromophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-isopropyl-N-methylbenzenesulfonamide;    MS (ESI) 540 (MH⁺);-   biphenyl-4-sulfonic acid    {1-[3-(4-bromophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-methylamide;    MS (ESI) 574 (MH⁺);-   benzo[1,3]dioxole-5-carboxylic acid    {1-[3-(4-bromophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-methylamide;    MS (ESI) 506 (MH⁺);-   N-{1-[3-(4-bromophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methyl-4-trifluoromethylbenzenesulfonamide;    MS (ESI) 566 (MH⁺); and-   N-{1-[3-(4-bromophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-tert-butyl-N-methylbenzamide;    MS (ESI) 518 (MH⁺).

Example 13 Preparation of2-(1-methylaminoethyl)-3-phenyl-3H-quinazolin-4-one and RelatedCompounds

A. In a similar manner as described above in Example 3 and Example 5,but replacing p-anisidine with aniline, the title compound was prepared;MS (ESI) 280 (MH⁺).

B. In a similar manner as described above, but replacing p-anisidinewith 4-fluoroaniline, the following compound was prepared:

-   3-(4-fluorophenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one; MS    (ESI) 298 (MH⁺).

C. In a similar manner as described above in Example7,2-(1-methylaminoethyl)-3-phenyl-3H-quinazolin-4-one, prepared asdescribed above in Paragraph A, was condensed with benzenesulfonylchloride to yieldN-methyl-N-[1-(4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl]benzenesulfonamide;MS (ESI) 420 (MH⁺).

D. In a similar manner as described above, but replacing benzenesulfonylchloride with the appropriate starting material, the following compoundswere made:

-   4-methoxy-N-methyl-N-[1-(4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl]benzenesulfonamide;    MS (ESI) 450 (MH⁺);-   4,N-dimethyl-N-[1-(4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl]benzenesulfonamide;    MS (ESI) 434 (MH⁺);-   4-chloro-N-methyl-N-[1-(4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl]benzenesulfonamide;    MS (ESI) 454 (MH⁺);-   4-tert-butyl-N-methyl-N-[1-(4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl]benzenesulfonamide;    MS (ESI) 476 (MH⁺);-   4-isopropyl-N-methyl-N-[1-(4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl]benzenesulfonamide;    MS (ESI) 462 (MH⁺);-   biphenyl-4-sulfonic acid methyl-[1-(4-oxo-3-phenyl-3,    dihydroquinazolin-2-yl)ethyl]amide; MS (ESI) 496 (MH⁺);-   4-tert-butyl-N-methyl-N-[1-(4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl]benzamide;    MS (ESI) 440 (MH⁺);-   benzo[1,3]dioxole-5-carboxylic acid    methyl-[1-(4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl]amide; MS    (ESI) 428 (MH⁺); and-   N-methyl-N-[1-(4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl]-4-trifluoromethylbenzenesulfonamide;    MS (ESI) 488 (MH⁺).

E. In a similar manner as described above in Paragraph A, but replacingbut replacing fp-anisidine with 4-chloroaniline, the following compoundwas prepared:

-   3-(4-chlorophenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one; MS    (ESI) 314 (MH⁺).

F. In a similar manner as described above in Example 7,3-(4chlorophenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one was condensedwith o-anisoyl chloride to yieldN-{1-[3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}2-methoxy-N-methylbenzamide;MS (ESI) 448 (MH⁺).

G. In a similar manner as described above in Paragraph F, but replacingo-anisoyl chloride with the appropriate starting material, the followingcompounds were made:

-   N-{1-[3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-3-methoxy-N-methylbenzamide;    MS (ESI) 448 (MH⁺);-   N-{1-[3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-methoxy-N-methylbenzamide:    MS (ESI) 448 (MH⁺);-   benzo[1,3]dioxole-5-carboxylic acid    {1-[3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;    MS (ESI) 462 (MH⁺);-   N-{1-[3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methyl-terephthalamic    acid methyl ester; MS (ESI) 476 (MH⁺);-   4-tert-butyl-N-{1-[3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzamide;    MS (ESI) 474 (MH⁺);-   4-tert-butyl-N-{1-[3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 510 (MH⁺);-   N-{1-[3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-methoxy-N-methylbenzenesulfonamide;    MS (ESI) 484 (MH⁺); and-   nonanoic acid    {1-[3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;    MS (ESI) 454 (MH⁺).

H. In a similar manner as described above in Example 3, Example 5 andExample 7, but replacing p-anisidine with 4-aminobenzonitrile, thefollowing compound was prepared:

-   4-tert-butyl-N-{1-[3-(4-cyanophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 501 (MH⁺).

I.4-tert-Butyl-N-{1-[3-(4-cyanophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide,prepared as described above in Paragraph H, was hydrolyzed withconcentrated HCl at reflux to yield4-(2-{1-[(4-tert-butyl-benzenesulfonyl)methylamino]ethyl}-4-oxo-4H-quinazolin-3-yl)-benzoicacid; MS (ESI) 520 (MH⁺).

J. In a similar manner as described above in Example 3 and Example 5,but replacing p-anisidine with 3,5-dimethylaniline, the followingcompound was made:

-   3-(3,5-dimethylphenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one;    MS (ESI) 308 (MH⁺).

K. In a similar manner as described above in Paragraph J, but replacing4-tert-butylbenzenesulfonyl chloride with the appropriate startingmaterial, the following compounds were made:

-   4-tert-butyl-N-{1-[3-(3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}N-methylbenzamide;    MS (ESI) 468 (MH⁺);-   benzo[1,3]dioxole-5-carboxylic acid    {1-[3-(3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;    MS (ESI) 456 (MH⁺);-   4-tert-butyl-N-{1-[3-(3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 504 (MH⁺);-   N-{1-[3-(3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-isopropyl-N-methylbenzenesulfonamide;    MS (ESI) 490 (MH⁺);-   biphenyl-4-sulfonic acid    {1-[3-(3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;    MS (ESI) 524 (MH⁺);-   N-{1-[3-(3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4,N-dimethylbenzenesulfonamide;    MS (ESI) 462 (MH⁺);-   N-{1-[3-(3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-methoxy-N-methylbenzenesulfonamide;    MS (ESI) 478 (MH⁺);-   N-{1-[3-(3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 448 (MH⁺);-   4-chloro-N-{1-[3-(3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;    MS (ESI) 482 (MH⁺); and-   N-{1-[3-(3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methyl-4-trifluoromethylbenzenesulfonamide;    MS (ESI) 516 (MH⁺).

L. In a similar manner as described above in Example 3 and Example 5,but replacing p-anisidine with 4-dimethylaminoaniline, the followingcompound was made:

-   3-(4-dimethylamino-phenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one;    MS (ESI) 323 (MH⁺).

M. In a similar manner as described above in Example7,3-(4-dimethylaminophenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one,as prepared above in Paragraph L, was condensed with4-tert-butylbenzenesulfonyl chloride to yield4-tert-butyl-N-{1-[3-(4-dimethylamino-phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;MS (ESI) 519 (MH⁺).

N. In a similar manner as described above in Paragraph M, but replacing4-tert-butylbenzenesulfonyl chloride with the appropriate startingmaterial, the following compounds were made:

-   N-{1-[3-(4-dimethylamino-phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-isopropyl-N-methylbenzenesulfonamide;    MS (ESI) 505 (MH⁺);-   biphenyl-4-sulfonic acid    {1-[3-(4-dimethylamino-phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;    MS (ESI) 539 (MH⁺);-   benzo[1,3]dioxole-5-carboxylic acid    {1-[3-(4-dimethylamino-phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;    MS (ESI) 471 (MH⁺); and-   4-tert-butyl-N-{1-[3-(4-dimethylamino-phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzamide;    MS (ESI) 483 (MH⁺).

Example 14 Preparation of4-tert-butyl-N-[3-(2,4-dimethylphenyl)₄-oxo-3,4-dihydroquinazolin-2-ylmethyl]-N-methylbenzenesulfonamideand Related Compounds

A. In a similar manner as described above in Example 3 and Example 5,but with the appropriate starting materials, the following compound wasprepared:

-   3-(2,4-dimethylphenyl)-2-methylamino-methyl-3H-quinazolin-4-one; MS    (ESI) 294 (MH⁺)

B. In a similar manner as described above in Example7,3-(2,4-dimethylphenyl)-2-methylamino-methyl-3H-quinazolin-4-one wascondensed with 4-tert-butylbenzenesulfonyl chloride to yield the titlecompound, MS (ESI) 490 (MH⁺)

C. In a similar manner as described above, but replacing4-tert-butylbenzenesulfonyl chloride with the appropriate startingmaterial, the following compounds were made:

-   benzo[1,3]dioxole-5-carboxylic acid    [3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]methylamide;    MS (ESI) 442 (MH⁺);-   4-tert-butyl-N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-N-methylbenzamide;    MS (ESI) 454 (MH⁺);-   N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-4-methoxy-N-methylbenzenesulfonamide;    MS (ESI) 464 (MH⁺);-   4-chloro-N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-N-methylbenzenesulfonamide;    MS (ESI) 468 (MH⁺);-   octane-1-sulfonic acid    [3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]methylamide;    MS (ESI) 470 (MH⁺);-   quinoline-8-sulfonic acid [3-(2,4-dimethylphenyl)-4-oxo-3,4    dihydroquinazolin-2-ylmethyl]methylamide; MS (ESI) 485 (MH⁺);-   naphthalene-1-sulfonic acid    [3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]methylamide;    MS (ESI) 484 (MH⁺);-   2-naphthalen-1-yl-ethanesulfonic acid    [3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]methylamide;    MS (ESI) 512 (MH⁺);-   N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-2,N-dimethylbenzenesulfonamide;    MS (ESI) 448 (MH⁺);-   N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-3,N-dimethylbenzenesulfonamide;    MS (ESI) 448 (MH⁺);-   N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-4,N-dimethylbenzenesulfonamide;    MS (ESI) 448 (MH⁺);-   N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-N-methyl-C-phenyl-methanesulfonamide;    MS (ESI) 448 (MH⁺);-   N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-N-methyl-3-trifluoromethylbenzenesulfonamide;    MS (ESI) 502 (MH⁺);-   N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-N-methyl-4-trifluoromethoxy-benzenesulfonamide;    MS (ESI) 518 (MH⁺);-   N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-2,5,N-trimethylbenzenesulfonamide;    MS (ESI) 462 (MH⁺);-   N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-3,4-dimethoxy-N-methylbenzenesulfonamide;    MS (ESI) 494 (MH⁺);-   N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-2,4,6,N-tetramethylbenzenesulfonamide;    MS (ESI) 476 (MH⁺);-   2-phenyl-ethenesulfonic acid [3-(2,4-dimethylphenyl)-4-oxo-3,4    dihydroquinazolin-2-ylmethyl]methylamide; MS (ESI) 460 (MH⁺);-   2,2,5,6,8-pentamethyl-chroman-7-sulfonic acid    [3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]methylamide;    MS (ESI) 560 (MH⁺);-   thiophene-2-sulfonic acid    [3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]methylamide;    MS (ESI) 440 (MH⁺);-   C-(7,7-dimethyl-2-oxo-bicyclo[2.2.1]hept-1-yl)-N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-N-methyl-methanesulfonamide;    MS (ESI) 508 (MH⁺);-   N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-3,4-difluoro-N-methylbenzenesulfonamide;    MS (ESI) 470 (MH⁺);-   3-chloro-N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-2,N-dimethylbenzenesutfonamide;    MS (ESI) 482 (MH⁺);-   N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-5-fluoro-2,N-dimethylbenzenesulfonamide;    MS (ESI) 466 (MH⁺);-   N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-N-methyl-4-trifluoromethylbenzenesulfonamide;    MS (ESI) 502 (MH⁺);-   N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-3-fluoro-N-methylbenzenesulfonamide;    MS (ESI) 452 (MH⁺);-   2,4,6-trichloro-N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-N-methylbenzenesulfonamide;    MS (ESI) 536 (MH⁺);-   3-chloro-N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-4-fluoro-N-methylbenzenesulfonamide;    MS (ESI) 486 (MH⁺);-   2-chloro-N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-N-methylbenzenesulfonamide;    MS (ESI) 468 (MH⁺);-   5-chloro-N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-2-methoxy-N-methylbenzenesulfonamide;    MS (ESI) 498 (MH⁺);-   N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-2,5-dimethoxy-N-methylbenzenesulfonamide;    MS (ESI) 494 (MH⁺);-   N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-2,3,4-trifluoro-N-methylbenzenesulfonamide;    MS (ESI) 488 (MH⁺);-   3-chloro-N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-N-methylbenzenesulfonamide;    MS (ESI) 468 (MH⁺);-   biphenyl-4-sulfonic acid    [3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]methylamide;    MS (ESI) 510 (MH⁺);-   4-cyano-N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-N-methylbenzenesulfonamide;    MS (ESI) 459 (MH⁺):-   4-butyl-N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-N-methylbenzenesulfonamide;    MS (ESI) 490 (MH⁺);-   N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-4-(1,1-dimethyl-propyl)-N-methylbenzenesulfonamide;    MS (ESI) 504 (MH⁺);-   N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-4-isopropyl-N-methylbenzenesulfonamide;    MS (ESI) 476 (MH⁺);-   4-butoxy-N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-N-methylbenzenesulfonamide;    MS (ESI) 506 (MH⁺);-   N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-3-methoxy-N-methylbenzenesulfonamide;    MS (ESI) 464 (MH⁺);-   N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-2-methoxy-4,N-dimethylbenzenesulfonamide;    MS (ESI) 478 (MH⁺);-   4-chloro-N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-2,5,N-trimethylbenzenesulfonamide;    MS (ESI) 496 (MH⁺);-   N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-N-methylmethanesulfonamide;    MS (ESI) 372 (MH⁺);-   butane-1-sulfonic acid    [3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]methylamide;    MS (ESI) 414 (MH⁺);-   3-chloropropane-1-sulfonic acid [3-(2,4-dimethylphenyl)-4-oxo-3,4    dihydroquinazolin-2-ylmethyl]methylamide; MS (ESI) 434 (MH⁺);-   N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-N-methyl-3,5-bis-trifluoromethylbenzenesulfonamide;    MS (ESI) 570 (MH⁺); and-   N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-N-methyl-4-nitrobenzenesulfonamide;    MS (ESI) 479 (MH⁺).

Example 15 Time Resolved Fluorescence Resonance Energy Transfer(TR-FRET) Assay

The FRET assay was performed by incubating 8 nM of GST-FXR-LBD(comprising glutathione-S-transferase fused in frame to the FXR LBD,(amino acids 244-471 of human FXR), 8 nM of Europium-labeled anti-GSTantibody (Wallac/PE Life Sciences Cat#AD0064), 16 nM biotin-SRC-1peptide [5′-biotin-CPSSHSSLTERHKILHRLLQEGSPS-CONH2], 20 nM APC-SA[allophycocyanin conjugated streptavidin] (Wallac/PE Life Sciences, Cat#AD0059A) in FRET assay buffer (20 mM KH₂PO₄/K₂HPO₄ (pH 7.3), 150 mMNaCl, 2 mM CHAPS, 2 mM EDTA, 1 mM DTT) in the presence of the testcompound(s) for 2-4 hours at room temperature. Data was collected usingan UL Analyst with readings at 615 nm and 665 nm after a delay of 65 μsand an excitation wavelength of 330 nm.

Example 16 FXR Co-Transfection Assay

The basic co-transfection protocol for measuring FXR activity is asfollows. CV-1 African Green Monkey Kidney cells are plated 24 hoursbefore transfection to achieve approximately 70-80 percent confluency.Cells are transfected with CMX-hFXR, CMX-RXRα, Luc12 reporter(ECREx7-Tk-Luciferase), and a CMX-p-Galactosidase expression vector (SeeWO 00/76523). The transfection reagent used is DOTAP (BoehringerMannheim). Cells are incubated with the DOTAP/DNA mixture for 5 hoursafter which the cells are harvested and plated onto either 96 well or384 well plates containing the appropriate concentration of testcompound. The assay is allowed to continue for an additional 18-20hours, after which the cells are lysed, with lysis buffer (1% triton X100, 10% glycerol, 5 mM Dithiothreitol, 1 mM EGTA, 25 mM Tricine, pH7.8) and the luciferase activity is measured in the presence ofLuciferase assay buffer (0.73 mM ATP, 22.3 mM Tricine, 0.11 mM EGTA,0.55 mM Luciferin, 0.15 mM Coenzyme A, 0.5 mM HEPES, 10 mM Magnesiumsulphate) on a standard luminomter plate reader (PE Biosystems,NorthStar Reader).

Example 17 In Vivo Studies

In order to evaluate direct regulation of key target genes by thecompounds of the invention, animals are administered a single oral doseof the test compound and tissues collected at six or fifteen hours afterdose. Male C57BL/6 mice (n=8) are dosed by oral gavage with vehicle orcompound. At six and fifteen hours after the dose, animals are bled viathe retro orbital sinus for plasma collection. Animals are theneuthanized and tissues, such as liver and intestinal mucosa arecollected and snap frozen for further analysis. Plasma is analyzed forlipid parameters, such as total cholesterol, HDL cholesterol andtriglyceride levels. RNA is extracted for frozen tissues and can beanalyzed by quantitative real time PCR for regulation of key targetgenes. To identify specificity of target gene regulation by FXR, knockout mice (FXR^(−/−)) and C57BL/6 wild-type controls maybe used in thissame protocol.

To compare the effects of compounds on plasma cholesterol andtriglycerides, animals are dosed with compound for one week and plasmalipid levels are monitored throughout the study. Male C57BL/6 mice (n=8)are dosed daily by oral gavage with vehicle or compound. Plasma samplesare taken on day −1 (in order to group animals), day 1, 3, and 7.Samples are collected three hours after the daily dose. On day 7 of thestudy, following plasma collection, animals are euthanized and tissues,such as liver and intestinal mucosa are collected and snap frozen forfurther analysis. Plasma is analyzed for lipid parameters, such as totalcholesterol, HDL cholesterol and triglyceride levels. RNA is extractedfor frozen tissues and can be analyzed by quantitative real time PCR forregulation of key target genes. To identify specificity of target generegulation by FXR knockout mice and C57BL/6 wild-type controls maybeused in this same protocol.

Evaluation of compounds to inhibit cholesterol absorption is done viameasurement of labeled cholesterol in feces. Male A129 mice (n=7) aredosed daily by oral gavage with vehicle or compound for 7 days. On day 7of the study, animals are administered [¹⁴C]-cholesterol and[³H]-sitostanol by oral gavage. Animals are individually housed on wireracks for the next 24 hours in order to collect feces. Feces are thendried and ground to a fine powder. Labeled cholesterol and sitostanolare extracted from the feces and ratios of the two are counted on aliquid scintillation counter in order to evaluate the amount ofcholesterol absorbed by the individual animal.

Results of Examples 15 and 16

Both the FXR/ECREx7 co-transfection assay (Example 15) and the TR-FRETassay (Example 16) can be used to establish the EC₅₀/IC₅₀ values forpotency and percent activity or inhibition for efficacy. Efficacydefines the activity of a compound relative to a high control(chenodeoxycholic acid, CDCA) or a low control (DMSO/vehicle). The doseresponse curves are generated from an 8 point curve with concentrationsdiffering by ½ LOG units. Each point represents the average of 4 wellsof data from a 384 well plate. The curve for the data is generated byusing the equation:

Y=Bottom+(Top−Bottom)/(1+10̂((Log EC50−X)*HillSlope))

The EC₅₀/IC₅₀ is therefore defined as the concentration at which anagonist or antagonist elicits a response that is half way between theTop (maximum) and Bottom (baseline) values. The EC₅₀/IC₅₀ valuesrepresented are the averages of at least 3 independent experiments. Thedetermination of the relative efficacy or % control for an agonist is bycomparison to the maximum response achieved by chenodeoxycholic acidthat is measured individually in each dose response experiment.

For the antagonist assay, CDCA is added to each well of a 384 well plateto elicit a response. The % inhibition for each antagonist is thereforea measurement of the inhibition of the activity of CDCA In this example,100% inhibition would indicate that the activity of CDCA has beenreduced to baseline levels, defined as the activity of the assay in thepresence of DMSO only.

Most of the compounds disclosed herein and tested exhibited activity inat least one of the above assays (EC₅₀ or IC₅₀ less than 10 μM). Mostshowed activity at below 1 μM. For example,4-tert-butyl-N-{1-[3-(4-methoxyphenyl)-4-oxo-6-thiophen-2-yl-3,4-dihydroquinazolin-2-yl]ethyl}N-methylbenzenesulfonamide(Example 9) shows an EC50 of about 600 nM and a % efficacy of about 110%in the co-transfection assay; and4-tert-butyl-N-{1-[6-methoxy-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide(Example 7) shows an EC₅₀ of about 300 nM and a % efficacy of about 190%in the co-transfection assay.

Since modifications will be apparent to those of skill in this art, itis intended that this invention be limited only by the scope of theappended claims.

1. A compound of formula (I):

wherein: m is an integer from 0 to 4; R¹ is hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkylalkyl, optionallysubstituted heterocyclylalkyl, —OR⁷ or —N(R⁸)R⁹, with the proviso thatR¹ is not 3- or 4-(1,1,1,1,3,3,3-hexafluoro-2-hydroxy-2-propyl)phenyl;R², R⁴, R⁵ and R⁶ are selected from (a) and (b) as follows: (a) R² andR⁶ are selected from (i) and (ii) as follows: (i) R² and R⁶ are eachindependently hydrogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted cycloalkyl, optionally substituted heterocyclyl, optionallysubstituted aralkyl, optionally substituted heteroaralkyl, optionallysubstituted cycloalkylalkyl, or optionally substitutedheterocyclylalkyl; or (ii) R² and R⁶ together form optionallysubstituted alkylene or optionally substituted alkenylene; and R⁴ and R⁵are selected from (i) and (ii) as follows: (i) R⁴ and R⁵ are eachindependently selected from hydrogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted cycloalkyl, optionally substituted heterocyclyl,optionally substituted aralkyl, optionally substituted heteroaralkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocyclylalkyl, —N(R⁸)R⁹), —OR⁷, —S(O)_(j)R¹¹ where j is 1 or 2,—B(R²²)₂, —P(R²²)₂, —P(O)(R²²)₂ and —C(E)R²³, where E is selected fromO, S and NR⁷; or (ii) R⁴ and R⁵ together form optionally substitutedalkylene, optionally substituted alkenylene, optionally substitutedalkyleneoxyalkylene or optionally substituted alkyleneazaalkylene; or(b) R² and R⁵, or R² and R⁴, or R⁶ and R⁵, or R⁶ and R⁴, together form a4, 5, 6 or 7 membered optionally substituted heterocyclyl group, or a 5or 6 membered optionally substituted heteroaryl group; and the remainderof R², R⁴, R⁵ and R⁶ are each independently selected as in (i) above;each R³ is independently selected from the group consisting of halo,pseudohalo, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, optionally substituted aralkyl,optionally substituted heteroaralkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocyclylalkyl, —N(R¹²)R¹³,—OR¹⁴, —C(E)R¹⁵ where E is O, S or NR⁷, and —S(O)_(y)R¹⁶ where y is 0, 1or 2; or any two R³ groups, which substitute adjacent carbons on thering, together form optionally substituted alkylene, optionallysubstituted alkenylene, optionally substituted alkylenedioxy, optionallysubstituted thioalkylenoxy, or optionally substituted alkylenedithioxy;each R⁷ is independently selected from the group consisting of hydrogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkylalkyl, and optionallysubstituted heterocyclylalkyl; R⁸ and R⁹ are each independently selectedfrom hydrogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, optionally substituted aralkyl,optionally substituted heteroaralkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocyclylalkyl, —S(O)_(j)R¹⁰where j is 1 or 2, and —C(M)R¹¹, where M is selected from O and S; or R⁸and R⁹ together form alkylene, alkenylene, alkyleneoxyalkylene oralkyleneazaalkylene; each R¹⁰ is independently selected from the groupconsisting of optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, optionally substituted aralkyl,optionally substituted heteroaralkyl, optionally substitutedcycloalkylalkyl, and optionally substituted heterocyclylalkyl; each R¹¹is independently selected from the group consisting of optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkylalkyl, optionallysubstituted heterocyclylalkyl, —OR¹⁰ and —N(R⁷)₂; R¹² and R¹³ are eachindependently selected from hydrogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted cycloalkyl, optionally substituted heterocyclyl,optionally substituted aralkyl, optionally substituted heteroaralkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocyclylalkyl, —C(M)R¹⁷ where M is O or S, and —S(O)_(j)R¹⁸ where jis 1 or 2; or R¹² and R¹³ together form optionally substituted alkylene,optionally substituted alkenylene, optionally substitutedalkyleneoxyalkylene or optionally substituted alkyleneazaalkylene; R¹⁴is hydrogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, optionally substituted aralkyl,optionally substituted heteroaralkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocyclylalkyl or —C(M)R¹⁷where M is O or S; R¹⁵ is hydrogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted cycloalkyl, optionally substituted heterocyclyl,optionally substituted aralkyl, optionally substituted heteroaralkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocyclylalkyl, —OH, —OR¹⁴ or —N(R¹²)R¹³; R¹⁶ is hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkylalkyl, optionallysubstituted heterocyclylalkyl, —OH, —OR¹⁹ or —N(R²⁰)R²¹; R¹⁷ ishydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted cycloalkyl, optionallysubstituted heterocyclyl, optionally substituted aralkyl, optionallysubstituted heteroaralkyl, optionally substituted cycloalkylalkyl,optionally substituted heterocyclylalkyl, —OR¹⁹ or —N(R²⁰)R²¹; R¹⁸ isoptionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkylalkyl, optionallysubstituted heterocyclylalkyl, —OR¹⁹ or —N(R²⁰)R²¹; R¹⁹ is alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl,heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; R²⁰ andR²¹ are each independently selected from hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,aryl, heteroaryl, aralkyl and heteroaralkyl, or R²⁰ and R²¹ togetherform alkylene, alkenylene, alkyleneoxyalkylene or alkyleneazaalkylene;each R²² is independently selected from the group consisting ofoptionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkylalkyl, optionallysubstituted heterocyclylalkyl, —OR⁷ and —N(R⁷)₂; R²³ is hydrogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkylalkyl, optionallysubstituted heterocyclylalkyl, —OR¹⁰, —N(R⁷)₂, or —N(R⁷)N(R⁷)₂; whereineach of the above R¹-R²³ groups, when substituted, are substituted withone or more substituents each independently selected from Q¹, where Q¹is halo, pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl,mercapto, carboxy, carboxyalkyl, alkyl, haloalkyl, polyhaloalkyl,aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds,alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl,aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl,alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene,alkylcarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyl, arylcarbonyl,heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl,aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl,aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl,diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy,heteroaryloxy, heteroaralkoxy, heterocyclyloxy, heterocyclylalkoxy,cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy,alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy,aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl,alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl,alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino,arylamino, diarylamino, alkylarylamino, alkylcarbonylamino,alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino,arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺(R²⁴)₃, —P(R²⁵)₂, —P(O)(R²⁵)₂, —OP(O)(R²⁵)₂,—N(R²⁴)C(O)R²⁶, dialkylphosphonyl, alkylarylphosphonyl,diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio,perfluoroalkylthio, carboxyalkylthio, thiocyano, isothiocyano,alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy,hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy,alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy,diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl,alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl,alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl,arylaminosulfonyl, diarylaminosulfonyl or alkylarylaminosulfonyl; or twoQ¹ groups, which substitute atoms in a 1,2 or 1,3 arrangement, togetherform alkylenedioxy (i.e., —O—(CH₂)_(y)—O—), thioalkylenoxy (i.e.,—S—(CH₂)_(y)—O—) or alkylenedithioxy (i.e., —S—(CH₂)_(y)—S—) where y is1 or 2; or two Q¹ groups, which substitute the same atom, together formalkylene; each R²⁴ is independently selected from the group consistingof hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl and heterocyclylalkyl; each R²⁵ is independently selectedfrom the group consisting of hydroxy, alkoxy, aralkoxy, alkyl,heteroaryl, heterocyclyl, aryl and —N(R²⁷)R²⁸ R²⁶ is alkoxy, aralkoxy,alkyl, heteroaryl, heterocyclyl, aryl or —N(R²⁷)R²⁸R²⁷ and R²⁸ are eachindependently hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkylor heterocyclyl, or R²⁷ and R²⁸ together form alkylene, azaalkylene,oxaalkylene or thiaalkylene; and each Q¹ is optionally substituted byone or more substituents selected from Q²; where each Q² isindependently halo, pseudohalo, hydroxy, oxo, thia, nitrile, nitro,formyl, mercapto, carboxy, carboxyalkyl, alkyl, haloalkyl,polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl,aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl,dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene,arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl,aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl,arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl,arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy,heterocyclyloxy, heterocyclylalkoxy, cycloalkoxy, perfluoroalkoxy,alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy,aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy,aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy,dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy,diarylaminocarbonyloxy, guanidino, isothioureido, amidino, alkylamidino,arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl,arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl,alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino,arylamino, diarylamino, alkylarylamino, alkylcarbonylamino,alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino,arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺(R²⁴)₃, —P(R²⁵)₂, —P(O)(R²⁵)₂, —OP(O)(R²⁵)₂,—N(R²⁴)C(O)R²⁶, dialkylphosphonyl, alkylarylphosphonyl,diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio,perfluoroalkylthio, carboxyalkylthio, thiocyano, isothiocyano,alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy,hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy,alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy,diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl,alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl,alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl,arylaminosulfonyl, diarylaminosulfonyl or alkylarylaminosulfonyl; or twoQ² groups, which substitute atoms in a 1,2 or 1,3 arrangement, togetherform alkylenedioxy (i.e., —O—(CH₂)_(y)—O—), thioalkylenoxy (i.e.,—S—(CH₂)_(y)—O—) or alkylenedithioxy (i.e., —S—(CH₂)_(y)—S—) where y is1 or 2; or two Q² groups, which substitute the same atom, together formalkylene, where R²⁴, R²⁵, R²⁶, R²⁷ and R²⁸ are as defined above; as astereoisomer, racemate or mixture thereof; or as a pharmaceuticallyacceptable derivative thereof; with the proviso that the compound offormula (I) can not beN-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]benzamide.2. The compound of claim 1 wherein the compound of formula (I) is acompound of formula (II):

wherein: n is an integer from 0 to 5; m is an integer from 0 to 4; eachR^(1a) and R³ are independently selected from the group consisting ofhalo, pseudohalo, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, optionally substituted aralkyl,optionally substituted heteroaralkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocyclylalkyl, —N(R¹²)R¹³,—OR¹⁴, —C(E)R¹⁵ where E is O, S or NR⁷, and —S(O)_(y)R¹⁶ where y is 0, 1or 2, with the proviso that R^(1a) is not 3- or 4-C(OH)(CF₃)₂; or anytwo R^(1a) groups or R³ groups, which substitute adjacent carbons on thering, together with atoms to which they are attached, form optionallysubstituted cycloalkyl, optionally substituted heterocyclyl, optionallysubstituted heteroaryl, or optionally substituted aryl; R², R⁴, R⁵ andR⁶ are selected from (a) and (b) as follows: (a) R² and R⁶ are selectedfrom (i) and (ii) as follows: (i) R² and R⁶ are each independentlyhydrogen or optionally substituted alkyl; or (ii) R² and R⁶ togetherform alkylene or alkenylene; R⁴ and R⁵ are selected from (i) and (ii) asfollows: (i) R⁴ and R⁵ are each independently selected from hydrogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkylalkyl, optionallysubstituted heterocyclylalkyl, —N(R⁸)R⁹, —OR⁷, S(O)_(j)R¹¹ where j is 1or 2, —B(R²²)₂, —P(R²²)₂, —P(O)(R²²)₂, and —C(E)R²³ where E is selectedfrom O, S and NR⁷; or (ii) R⁴ and R⁵ together form optionallysubstituted alkylene, optionally substituted alkenylene, optionallysubstituted alkyleneoxyalkylene or optionally substitutedalkyleneazaalkylene; (b) R² and R⁵, or R² and R⁴, or R⁶ and R⁵, or R⁶and R⁴, together form a 5, 6 or 7 membered optionally substitutedheterocyclyl group, or a 5 or 6 membered optionally substitutedheteroaryl group; and the remainder of R², R⁴, R⁵ and R⁶ are eachindependently selected as in (i) above; each R⁷ is independentlyselected from the group consisting of hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted cycloalkyl, optionally substituted heterocyclyl,optionally substituted aralkyl, optionally substituted heteroaralkyl,optionally substituted cycloalkylalkyl, and optionally substitutedheterocyclylalkyl; R⁸ and R⁹ are each independently selected fromhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted cycloalkyl, optionallysubstituted heterocyclyl, optionally substituted aralkyl, optionallysubstituted heteroaralkyl, optionally substituted cycloalkylalkyl,optionally substituted heterocyclylalkyl, —S(O)_(j)R¹⁰ where j is 1 or2, and —C(M)R¹¹, where M is selected from O and S; or R⁸ and R⁹ togetherform alkylene, alkenylene, alkyleneoxyalkylene or alkyleneazaalkylene;each R¹⁰ is independently selected from the group consisting ofoptionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkylalkyl, and optionallysubstituted heterocyclylalkyl; each R¹¹ is independently selected fromthe group consisting of optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted cycloalkyl, optionally substituted heterocyclyl, optionallysubstituted aralkyl, optionally substituted heteroaralkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocyclylalkyl,—OR¹⁰ and —N(R⁷)₂; R¹² and R¹³ are each independently selected fromhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted cycloalkyl, optionallysubstituted heterocyclyl, optionally substituted aralkyl, optionallysubstituted heteroaralkyl, optionally substituted cycloalkylalkyl,optionally substituted heterocyclylalkyl, —C(M)R¹⁷ where M is O or S,and —S(O)_(j)R¹⁴ where j is 1 or 2; or R¹² and R¹³ together formalkylene, alkenylene, alkyleneoxyalkylene or alkyleneazaalkylene; R¹⁴ ishydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted cycloalkyl, optionallysubstituted heterocyclyl, optionally substituted aralkyl, optionallysubstituted heteroaralkyl, optionally substituted cycloalkylalkyl,optionally substituted heterocyclylalkyl or —C(M)R¹⁷ where m is O or S;R¹⁵ is hydrogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, optionally substituted aralkyl,optionally substituted heteroaralkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocyclylalkyl, —OH, —OR¹⁹ or—N(R²⁰)R²¹; R¹⁶ is hydrogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted cycloalkyl, optionally substituted heterocyclyl, optionallysubstituted aralkyl, optionally substituted heteroaralkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocyclylalkyl,—OH, —OR¹⁹ or —N(R²⁰)R²¹; R¹⁷ is hydrogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted cycloalkyl, optionally substituted heterocyclyl,optionally substituted aralkyl, optionally substituted heteroaralkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocyclylalkyl, —OR¹⁹ or —N(R²⁰)R²¹; R¹⁸ is optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted cycloalkyl, optionally substituted heterocyclyl,optionally substituted aralkyl, optionally substituted heteroaralkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocyclylalkyl, —OR¹⁹ or —N(R²⁰)R²¹; R¹⁹ is alkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl,heteroaryl, aralkyl or heteroaralkyl; R²⁰ and R²¹ are each independentlyselected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl,aralkyl and heteroaralkyl, or R²⁰ and R² together form alkylene,alkenylene or alkyleneoxyalkylene; each R²² is independently selectedfrom the group consisting of optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted cycloalkyl, optionally substituted heterocyclyl, optionallysubstituted aralkyl, optionally substituted heteroaralkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocyclylalkyl,—OR⁷ and —N(R⁷)₂; R²³ is hydrogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted cycloalkyl, optionally substituted heterocyclyl,optionally substituted aralkyl, optionally substituted heteroaralkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocyclylalkyl, —OR¹⁰, —N(R⁷)₂, —N(R⁷)N(R⁷)₂; wherein each of theabove R¹-R²³ groups, when substituted, are substituted with one or moresubstituents each independently selected from Q¹, where Q¹ is halo,pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto,carboxy, carboxyalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl,diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl,heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl,triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl,heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl,aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl,aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl,diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy,heteroaryloxy, heteroaralkoxy, heterocyclyloxy, heterocyclylalkoxy,cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy,alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy,aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl,alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl,alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino,arylamino, diarylamino, alkylarylamino, alkylcarbonylamino,alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino,arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺(R²⁴)₃, —P(R²⁵)₂, —P(O)(R²⁵)₂, —OP(O)(R²⁵)₂,—N(R²⁴)C(O)R²⁶, dialkylphosphonyl, alkylarylphosphonyl,diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio,perfluoroalkylthio, carboxyalkylthio, thiocyano, isothiocyano,alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy,hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy,alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy,diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl,alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl,alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl,arylaminosulfonyl, diarylaminosulfonyl or alkylarylaminosulfonyl; or twoQ¹ groups, which substitute atoms in a 1,2 or 1,3 arrangement, togetherform alkylenedioxy (i.e., —O—(CH₂)_(y)—O—), thioalkylenoxy (i.e.,—S—(CH₂)_(y)—O—) or alkylenedithioxy (i.e., —S—(CH₂)_(y)—S—) where y is1 or 2; or two Q¹ groups, which substitute the same atom, together formalkylene; each R²⁴ is independently selected from the group consistingof hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl and heterocyclylalkyl; each R²⁵ is independently selectedfrom the group consisting of hydroxy, alkoxy, aralkoxy, alkyl,heteroaryl, heterocyclyl, aryl and —N(R²⁷)R²⁸, R²⁶ is alkoxy, aralkoxy,alkyl, heteroaryl, heterocyclyl, aryl or —N(R²⁷)R²⁸; R²⁷ and R²⁸ areeach independently hydrogen, alkyl, aralkyl, aryl, heteroaryl,heteroaralkyl or heterocyclyl, or R²⁷ and R²⁸ together form alkylene,azaalkylene, oxaalkylene or thiaalkylene; and each Q¹ is optionallysubstituted by one or more substituents selected from Q²; where each Q²is independently halo, pseudohalo, hydroxy, oxo, thia, nitrile, nitro,formyl, mercapto, carboxy, carboxyalkyl, alkyl, haloalkyl,polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl,aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl,dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene,arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl,aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl,arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl,arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy,heterocyclyloxy, heterocyclylalkoxy, cycloalkoxy, perfluoroalkoxy,alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy,aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy,aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy,dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy,diarylaminocarbonyloxy, guanidino, isothioureido, amidino, alkylamidino,arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl,arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl,alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino,arylamino, diarylamino, alkylarylamino, alkylcarbonylamino,alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino,arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺(R²⁴)₃, —P(R²⁵)₂, —P(O)(R²⁵)₂, —OP(O)(R²⁵)₂,—N(R²⁴)C(O)R²⁶, dialkylphosphonyl, alkylarylphosphonyl,diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio,perfluoroalkylthio, carboxyalkylthio, thiocyano, isothiocyano,alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy,hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy,alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy,diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl,alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl,alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl,arylaminosulfonyl, diarylaminosulfonyl or alkylarylaminosulfonyl; or twoQ² groups, which substitute atoms in a 1,2 or 1,3 arrangement, togetherform alkylenedioxy (i.e., —O—(CH₂)_(y)—O—), thioalkylenoxy (i.e.,—S—(CH₂)_(y)—O—) or alkylenedithioxy (i.e., —S—(CH₂)_(y)—S—) where y is1 or 2; or two Q² groups, which substitute the same atom, together formalkylene, where R²⁴, R²⁵R²⁶, R²⁷ and R²⁸ are as defined above; as astereoisomer, racemate or mixture thereof; or as a pharmaceuticallyacceptable derivative thereof.
 3. The compound of claim 2 wherein thecompound of formula (II) is a compound of formula (III):

wherein: n is an integer from 0 to 5; m is an integer from 0 to 4; t isan integer from 0 to 5; each R^(1a) is independently selected from thegroup consisting of alkyl, hydroxy, alkoxy, alkoxyalkoxy, aralkoxy,amino, alkylamino, dialkylamino, halo, haloalkyl, haloalkoxy, cyano,carboxy, alkoxycarbonyl, alkoxycarbonylalkoxy, heteroaryl, heterocyclyl,heterocyclylalkoxy, and aryl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, alkoxy, halo,cyano, carboxy, cyano, and alkoxycarbonyl); R² is hydrogen or alkyl′each R³ is independently selected from the group consisting of alkyl,alkoxy, halo, hydroxy, aralkoxy, alkoxycarbonylalkoxy, aryl (optionallysubstituted by one or more substituents independently selected from thegroup consisting of alkyl, halo, alkoxy, carboxy, alkoxycarbonyl,cyano), heteroaryl and heterocyclyl; R⁴ is hydrogen or alkyl; eachR^(5a) is independently selected from the group consisting of alkyl,alkoxy, halo, alkylcarbonyl, haloalkyl, haloalkoxy, aryl, cyano,carboxy, alkoxycarbonyl, nitro, and —N(R²⁴)C(O)R²⁶; or two adjacentR^(5a) groups form an aryl, heterocyclyl or heteroaryl; and R⁶ ishydrogen or alkyl.
 4. The compound of claim 3 wherein m is 0 or 1, n is1 and R^(1a) is independently selected from alkoxy, halo, haloalkyl,haloalkoxy, cyano, optionally substituted aryl, heterocyclyl andheteroaryl.
 5. The compound of claim 4 selected from the groupconsisting of the following:N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]benzenesulfonamide;N-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-4-methylbenzenesulfonamide;4-tert-butyl-N-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]benzenesulfonamide;4-methoxy-N-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]benzenesulfonamide;4-chloro-N-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]benzenesulfonamide;4-tert-butyl-N-{1-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;N-{1-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4,N-dimethylbenzenesulfonamide;4-({1-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-methyl-sulfamoyl)-benzoicacid;4-tert-butyl-N-{1-[3-(4-methoxyphenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-isopropyl-N-{1-[3-(4-methoxyphenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;biphenyl-4-sulfonic acid{1-[3-(4-methoxyphenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;N-{1-[3-(4-methoxyphenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4,N-dimethylbenzenesulfonamide;4-methoxy-N-{1-[3-(4-methoxyphenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-butyl-N-{1-[3-(4-methoxyphenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;N-{1-[3-(4-methoxyphenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methyl-4-trifluoromethylbenzenesulfonamide;2,4,6-trichloro-N-{1-[3-(4-methoxyphenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-tert-butyl-N-{1-[3-(4-methoxyphenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-isopropyl-N-{1-[3-(4-methoxyphenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;biphenyl-4-sulfonic acid{1-[3-(4-methoxyphenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;N-{1-[3-(4-methoxyphenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4,N-dimethylbenzenesulfonamide;4-methoxy-N-{1-[3-(4-methoxyphenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-butyl-N-{1-[3-(4-methoxyphenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;N-{1-[3-(4-methoxyphenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methyl-4-trifluoromethylbenzenesulfonamide;2,4,6-trichloro-N-{1-[3-(4-methoxyphenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-tert-butyl-N-{1-[3-(4-methoxyphenyl)-6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-isopropyl-N-{1-[3-(4-methoxyphenyl)-6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;biphenyl-4-sulfonic acid{1-[3-(4-methoxyphenyl)-6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;N-{1-[3-(4-methoxyphenyl)-6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4,N-dimethylbenzenesulfonamide;4-methoxy-N-{1-[3-(4-methoxyphenyl)-6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-butyl-N-{1-[3-(4-methoxyphenyl)-6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;N-{1-[3-(4-methoxyphenyl)-6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methyl-4-trifluoromethylbenzenesulfonamide;2,4,6-trichloro-N-{1-[3-(4-methoxyphenyl)-6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;N-{1-[7-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-isopropyl-N-methylbenzenesulfonamide;biphenyl-4-sulfonic acid{1-[7-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;N-{1-[7-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-methoxy-N-methylbenzenesulfonamide;N-{1-[7-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;N-{1-[7-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4,N-dimethylbenzenesulfonamide;N-{1-[7-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methyl-4-trifluoromethylbenzenesulfonamide;4-tert-butyl-N-{1-[6-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;N-{1-[6-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-isopropyl-N-methylbenzenesulfonamide;biphenyl-4-sulfonic acid{1-[6-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;N-{1-[6-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-methoxy-N-methylbenzenesulfonamide;N-{1-[6-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;N-{1-[6-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4,N-dimethylbenzenesulfonamide;N-{1-[6-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methyl-4-trifluoromethylbenzenesulfonamide;2,4,6-trichloro-N-{1-[6-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-tert-butyl-N-{1-[3-(4-methoxyphenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-isopropyl-N-{1-[3-(4-methoxyphenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;biphenyl-4-sulfonic acid{1-[3-(4-methoxyphenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;N-{1-[3-(4-methoxyphenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4,N-dimethylbenzenesulfonamide;4-methoxy-N-{1-[3-(4-methoxyphenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;benzo[1,3]dioxole-5-carboxylic acid{1-[3-(4-methoxyphenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;4-tert-butyl-N-{1-[3-(4-methoxyphenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzamide;4-butyl-N-{1-[3-(4-methoxyphenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;N-{1-[3-(4-methoxyphenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methyl-4-trifluoromethylbenzenesulfonamide;2,4,6-trichloro-N-{1-[3-(4-methoxyphenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-tert-butyl-N-{1-[8-methoxy-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-isopropyl-N-{1-[8-methoxy-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;biphenyl-4-sulfonic acid{1-[8-methoxy-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;4-tert-butyl-N-{1-[5-methoxy-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-isopropyl-N-{1-[5-methoxy-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;biphenyl-4-sulfonic acid{1-[5-methoxy-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;4-tert-butyl-N-{1-[6-methoxy-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-isopropyl-N-{1-[6-methoxy-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;biphenyl-4-sulfonic acid{1-[6-methoxy-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;4-tert-butyl-N-{1-[3-(3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-isopropyl-N-{1-[3-(3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;biphenyl-4-sulfonic acid{1-[3-(3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;4-tert-butyl-N-{1-[3-(2-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-isopropyl-N-{1-[3-(2-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;biphenyl-4-sulfonic acid{1-[3-(2-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;4-tert-butyl-N-{1-[8-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;N-{1-[8-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-isopropyl-N-methylbenzenesulfonamide;biphenyl-4-sulfonic acid{1-[8-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;4-tert-butyl-N-{1-[3-(4-ethoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-tert-butyl-N-{1-[3-(4-isopropoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-tert-butyl-N-{1-[3-(4-isobutoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-tert-butyl-N-{1-[3-(4-n-butoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-methoxy-N-{1-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-methoxy-N-{1-[3-(4-cyanophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-tert-butyl-N-{1-[7-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide.4-tert-butyl-N-{1-[3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide:N-{1-[3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-methoxy-N-methylbenzenesulfonamide;N-{1-[3-(4-bromophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-tert-butyl-N-methylbenzenesulfonamide:4-tert-butyl-N-{1-[3-(4-cyanophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-ethyl}-N-methylbenzenesulfonamide;N-{1-[3-(4-bromophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-isopropyl-N-methylbenzenesulfonamide:biphenyl-4-sulfonicacid-{1-[3-(4-bromophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;N-{1-[3-(4-bromophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-ethyl}-4,N-dimethylbenzenesulfonamide,N-{1-[3-(4-bromophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-chloro-N-methylbenzenesulfonamide;N-{1-[3-(4-bromophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methyl-4-trifluoromethylbenzenesulfonamide;4-tert-butyl-N-methyl-N-{1-[4-oxo-3-(4-trifluoromethoxyphenyl)-3,4-dihydroquinazolin-2-yl]ethyl}-benzenesulfonamide,4-isopropyl-N-methyl-N-{1-[4-oxo-3-(4-trifluoromethoxyphenyl)-3,4-dihydroquinazolin-2-yl]ethyl}-benzenesulfonamide,biphenyl-4-sulfonic acidmethyl-{1-[4-oxo-3-(4-trifluoromethoxyphenyl)-3,4-dihydroquinazolin-2-yl]ethyl}-amide;4-tert-butyl-N-{1-[3-(4-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide,N-{1-[3-(4-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-isopropyl-N-methylbenzenesulfonamide;biphenyl-4-sulfonic acid{1-[3-(4-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;4-tert-butyl-N-methyl-N-{1-[4-oxo-3-(4-trifluoromethylphenyl)-3,4-dihydroquinazolin-2-yl]ethyl}-benzenesulfonamide;4-isopropyl-N-methyl-N-{1-[4-oxo-3-(4-trifluoromethylphenyl)-3,4-dihydroquinazolin-2-yl]ethyl}-benzenesulfonamide;biphenyl-4-sulfonic acidmethyl-{1-[4-oxo-3-(4-trifluoromethylphenyl)-3,4-dihydroquinazolin-2-yl]ethyl}-amide;N-{1-[3-(4-bromophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;N-{1-[3-(4-bromophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-methoxy-N-methylbenzenesulfonamide;N-[1-(3-biphenyl-4-yl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl]-4-tert-butyl-N-methylbenzenesulfonamide;4-tert-butyl-N-{1-[3-(3′-methoxy-biphenyl-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-tert-butyl-N-{1-[3-(3′-chloro-biphenyl-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide:4-tert-butyl-N-methyl-N-{1-[3-(4′-methyl-biphenyl-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-benzenesulfonamide;4-tert-butyl-N-{1-[3-(2′-chloro-biphenyl-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-tert-butyl-N-{1-[3-(4′-chloro-biphenyl-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]-ethyl}-N-methylbenzenesulfonamide;4-tert-butyl-N-{1-[3-(2′-methoxy-biphenyl-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-tert-butyl-N-{1-[3-(4′-methoxy-biphenyl-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4′-(2-{1-[(4-tert-butylbenzenesulfonyl)methylamino]ethyl}-4-oxo-4H-quinazolin-3-yl)-biphenyl-4-carboxylicacid;4-tert-butyl-N-{1-[3-(4′-cyano-biphenyl-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-tert-butyl-N-methyl-N-{1-[4-oxo-3-(4-thiophen-3-ylphenyl)-3,4-dihydroquinazolin-2-yl]ethyl}benzenesulfonamide;4′-(2-{1-[(4-tert-butylbenzenesulfonyl)methylamino]ethyl}-4-oxo-4H-quinazolin-3-yl)-biphenyl-3-carboxylicacid methyl ester;4′-(2-{1-[(4-tert-butylbenzenesulfonyl)methylamino]ethyl}-4-oxo-4H-quinazolin-3-yl)-biphenyl-4-carboxylicacid methyl ester,4′-(2-{1-[(4-tert-butylbenzenesulfonyl)-methylamino]ethyl}-4-oxo-4H-quinazolin-3-yl)-biphenyl-3-carboxylicacid;4-tert-butyl-N-methyl-N-{1-[4-oxo-3-(4-pyrrolidin-1-ylphenyl)-3,4-dihydroquinazolin-2-yl]-ethyl}benzenesulfonamide;4-tert-butyl-N-methyl-N-{1-[4-oxo-3-(4-piperidin-1-yl-phenyl)-3,4-dihydroquinazolin-2-yl]ethyl}benzenesulfonamide;and4-tert-butyl-N-methyl-N-{1-[4-oxo-3-(4-thiophen-2-ylphenyl)-3,4-dihydroquinazolin-2-yl]ethyl}benzenesulfonamide.6. The compound of claim 3 wherein m is 0 or 1, n is 1, 2 or 3 and eachR^(1a) is selected from alkyl.
 7. The compound of claim 6 selected fromthe group consisting of the following: quinoline-8-sulfonic acid{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;naphthalene-1-sulfonic acid{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;naphthalene-2-sulfonic acid {1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;2-naphthalen-1-yl-ethanesulfonic acid{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-2,N-dimethylbenzenesulfonamide;N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-3,N-dimethylbenzenesulfonamide;N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4,N-dimethylbenzenesulfonamide;N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methyl-C-phenyl-methanesulfonamide;4-acetyl-N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methyl-3-trifluoromethylbenzenesulfonamide;N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methyl-4-trifluoromethoxy-benzenesulfonamide;N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-2,5,N-trimethylbenzenesulfonamide;N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-3,4-dimethoxy-N-methylbenzenesulfonamide;N-[4-({1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-methyl-sulfamoyl)-phenyl]-acetamide;N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-2,4,6,N-tetramethylbenzenesulfonamide;2-phenyl-ethenesulfonic acid{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;2,2,5,6,8-pentamethyl-chroman-7-sulfonic acid{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-3,4-difluoro-N-methylbenzenesulfonamide;3-chloro-N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-2,N-dimethylbenzenesulfonamide;N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-5-fluoro-2,N-dimethylbenzenesulfonamide;3,5-dimethyl-isoxazole-4-sulfonic acid{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methyl-4-trifluoromethylbenzenesulfonamide;N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-3-fluoro-N-methylbenzenesulfonamide;2,4,6-trichloro-N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;3-chloro-N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-fluoro-N-methylbenzenesulfonamide;2-chloro-N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;5-chloro-N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-2-methoxy-N-methylbenzenesulfonamide;N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-2,5-dimethoxy-N-methylbenzenesulfonamide;N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-2,3,4-trifluoro-N-methylbenzenesulfonamide;3-chloro-N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-cyano-N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-butyl-N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-(1,1-dimethyl-propyl)-N-methylbenzenesulfonamide;4-butoxy-N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-3-methoxy-N-methylbenzenesulfonamide;N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-2-methoxy-4,N-dimethylbenzenesulfonamide;4-chloro-N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-2,5,N-trimethylbenzenesulfonamide;N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methyl-methanesulfonamide;biphenyl-4-sulfonic acid{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-isopropyl-N-methylbenzenesulfonamide;N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-4-methylbenzenesulfonamide;4-tert-butyl-N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]benzenesulfonamide;N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-4-methoxy-benzenesulfonamide;N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-methoxy-N-methylbenzenesulfonamide;4-tert-butyl-N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-N-methylbenzenesulfonamide;N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-4-methoxy-N-methylbenzenesulfonamide;4-chloro-N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-N-methylbenzenesulfonamide;octane-1-sulfonic acid[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]methylamide;quinoline-8-sulfonic acid[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]methylamide;naphthalene-1-sulfonic acid[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]methylamide;N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-2,N-dimethylbenzenesulfonamide;N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-3,N-dimethylbenzenesulfonamide;N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-4,N-dimethylbenzenesulfonamide;N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-N-methyl-3-trifluoromethylbenzenesulfonamide;N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-N-methyl-4-trifluoromethoxy-benzenesulfonamide;N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-2,5,N-trimethylbenzenesulfonamide;N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-3,4-dimethoxy-N-methylbenzenesulfonamide;N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-2,4,6,N-tetramethylbenzenesulfonamide;2,2,5,6,8-pentamethyl-chroman-7-sulfonic acid[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]methylamide;N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-3,4-difluoro-N-methylbenzenesulfonamide;3-chloro-N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-2,N-dimethylbenzenesulfonamide;N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-5-fluoro-2,N-dimethylbenzenesulfonamide;N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-N-methyl-4-trifluoromethylbenzenesulfonamide;N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-3-fluoro-N-methylbenzenesulfonamide;2,4,6-trichloro-N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-N-methylbenzenesulfonamide;3-chloro-N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-4-fluoro-N-methylbenzenesulfonamide;2-chloro-N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-N-methylbenzenesulfonamide;5-chloro-N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-2-methoxy-N-methylbenzenesulfonamide;N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-2,5-dimethoxy-N-methylbenzenesulfonamide;N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-2,3,4-trifluoro-N-methylbenzenesulfonamide;3-chloro-N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-N-methylbenzenesulfonamide;biphenyl-4-sulfonic acid[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]methylamide;4-cyano-N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-N-methylbenzenesulfonamide;4-butyl-N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-N-methylbenzenesulfonamide;N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-4-(1,1-dimethyl-propyl)-N-methylbenzenesulfonamide;N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-4-isopropyl-N-methylbenzenesulfonamide;4-butoxy-N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-N-methylbenzenesulfonamide;N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-3-methoxy-N-methylbenzenesulfonamide;N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-2-methoxy-4,N-dimethylbenzenesulfonamide;4-chloro-N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-2,5,N-trimethylbenzenesulfonamide;N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-N-methyl-3,5-bis-trifluoromethylbenzenesulfonamide;andN-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-N-methyl-4-nitro-benzenesulfonamide;4-tert-butyl-N-{1-[3-(3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;N-{1-[3-(3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-isopropyl-N-methylbenzenesulfonamide;biphenyl-4-sulfonic acid{1-[3-(3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;N-{1-[3-(3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4,N-dimethylbenzenesulfonamide;N-{1-[3-(3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-methoxy-N-methylbenzenesulfonamide;N-{1-[3-(3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-chloro-N-{1-[3-(3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;N-{1-[3-(3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methyl-4-trifluoromethylbenzenesulfonamide;4-tert-butyl-N-{1-[3-(4-tert-butyl-phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;N-{1-[3-(4-tert-butyl-phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-isopropyl-N-methylbenzenesulfonamide;biphenyl-4-sulfonic acid{1-[3-(4-tert-butyl-phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;4-tert-butyl-N-methyl-N-[1-(4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]benzenesulfonamide;4-isopropyl-N-methyl-N-[1-(4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]benzenesulfonamide;biphenyl-4-sulfonic acidmethyl-[1-(4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]amide;4-tert-butyl-N-[1-(6-methoxy-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]-N-methylbenzenesulfonamide;4-tert-butyl-N-[1-(6-hydroxy-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]-N-methylbenzenesulfonamide;N-[1-(6-bromo-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]-4-tert-butyl-N-methylbenzenesulfonamide;biphenyl-4-sulfonic acid[1-(6-bromo-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]methylamide;N-[1-(6-bromo-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]-4-isopropyl-N-methylbenzenesulfonamide;N-[1-(6-benzyloxy-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]-4-tert-butyl-N-methylbenzenesulfonamide;4-tert-butyl-N-[1-(6-isobutoxy-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]-N-methylbenzenesulfonamide;N-[1-(6-butoxy-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]-4-tert-butyl-N-methylbenzenesulfonamide;(2-{1-[(4-tert-butylbenzenesulfonyl)methylamino]ethyl}-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-6-yloxy)aceticacid ethyl ester;4-tert-butyl-N-[1-(6-ethoxy-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]-N-methylbenzenesulfonamide;4-tert-butyl-N-{1-[3-(4-methoxyphenyl)-4-oxo-6-thiophen-3-yl-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-tert-butyl-N-methyl-N-[1-(4-oxo-6-phenyl-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]benzenesulfonamide;4-tert-butyl-N-{1-[3-(4-methoxyphenyl)-4-oxo-6-thiophen-2-yl-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-tert-butyl-N-methyl-N-{1-[3-(2′-methyl-biphenyl-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-benzenesulfonamide;4-tert-butyl-N-methyl-N-{1-[3-(3′-methyl-biphenyl-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-benzenesulfonamide;4-tert-butyl-N-methyl-N-[1-(4-oxo-6-o-tolyl-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]benzenesulfonamide;4-tert-butyl-N-methyl-N-[1-(4-oxo-3,6-di-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]benzenesulfonamide;4-tert-butyl-N-{1-[6-(2-chlorophenyl)-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-tert-butyl-N-{1-[6-(4-chlorophenyl)-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-tert-butyl-N-{1-[6-(2-methoxyphenyl)-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-tert-butyl-N-{1-[6-(3-methoxyphenyl)-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-tert-butyl-N-{1-[6-(4-methoxyphenyl)-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;3-(2-{1-[(4-tert-butyl-benzenesulfonyl)methylamino]ethyl}-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-6-yl)benzoicacid methyl ester;4-(2-{1-[(4-tert-butyl-benzenesulfonyl)methylamino]ethyl}-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-6-yl)-benzoicacid methyl ester;3-(2-{1-[(4-tert-butylbenzenesulfonyl)methylamino]ethyl}-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-6-yl)benzoicacid;4-tert-butyl-N-{1-[6-(4-cyanophenyl)-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-tert-butyl-N-methyl-N-[1-(6-morpholin-4-yl-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]benzenesulfonamide;and4-tert-butyl-N-{1-[3-(4-methoxyphenyl)-4-oxo-6-m-tolyl-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-tert-butyl-N-{1-[3-(4-methoxyphenyl)-4-oxo-6-pyrrolidin-1-yl-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-[2-{1-[(4-tert-butyl-benzenesulfonyl)methylamino]ethyl}-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl]benzoicacid;4-tert-butyl-N-methyl-N-[1-(4-oxo-6-piperidin-1-yl-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]benzenesulfonamide;and4-tert-butyl-N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide.8. (canceled)
 9. (canceled)
 10. The compound of claim 3 wherein m is 0or 1, n is 0 or 1 and each R^(1a) is selected from carboxy,dialkylamino, hydroxy, alkoxyalkoxy, alkoxycarbonylalkoxy, aralkoxy, andheterocyclylalkoxy.
 11. The compound of claim 10 selected from the groupconsisting of the following:4-(2-{1-[(4-tert-butyl-benzenesulfonyl)methylamino]ethyl}-4-oxo-4H-quinazolin-3-yl)-benzoicacid;4-tert-butyl-N-{1-[3-(4-dimethylamino-phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;N-{1-[3-(4-dimethylamino-phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-isopropyl-N-methylbenzenesulfonamide;biphenyl-4-sulfonic acid{1-[3-(4-dimethylamino-phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;4-tert-butyl-N-methyl-N-[1-(4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl]benzenesulfonamide;4-isopropyl-N-methyl-N-[1-(4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl]benzenesulfonamide;biphenyl-4-sulfonic acidmethyl-[1-(4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl]amide;N-methyl-N-[1-(4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl]benzenesulfonamide;4-methoxy-N-methyl-N-[1-(4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl]benzenesulfonamide;4,N-dimethyl-N-[1-(4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl]benzenesulfonamide;4-chloro-N-methyl-N-[1-(4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl]benzenesulfonamide;N-methyl-N-[1-(4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl]-4-trifluoromethylbenzenesulfonamide;N-{1-[3-(4-benzyloxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-tert-butyl-N-methylbenzenesulfonamide;N-{1-[3-(4-benzyloxy-phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-isopropyl-N-methylbenzenesulfonamide;biphenyl-4-sulfonic acid{1-[3-(4-benzyloxy-phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;4-tert-butyl-N-{1-[3-(4-hydroxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-tert-butyl-N-{1-[5-hydroxy-3-(4-hydroxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-tert-butyl-N-methyl-N-(1-{4-oxo-3-[4-(2-piperidin-1-yl-ethoxy)phenyl]-3,4-dihydroquinazolin-2-yl}ethyl)benzenesulfonamide;4-tert-butyl-N-methyl-N-(1-{3-[4-(2-morpholin-4-yl-ethoxy)phenyl]-4-oxo-3,4-dihydroquinazolin-2-yl}ethyl)benzenesulfonamide;[4-(2-{1-[(4-tert-butylbenzenesulfonyl)methylamino]ethyl}-4-oxo-4H-quinazolin-3-yl)phenoxy]aceticacid ethyl ester; and4-tert-butyl-N-(1-{3-[4-(2-methoxyethoxy)phenyl]-4-oxo-3,4-dihydroquinazolin-2-yl}ethyl)-N-methylbenzenesulfonamide.12. (canceled)
 13. (canceled)
 14. (canceled)
 15. The compound of claim 2wherein the compound of formula (II) is a compound of formula (V):

wherein: m is an integer from 0 to 4; n is an integer from 0 to 5; t isan integer from 0 to 5; each R^(1a) is selected from the groupconsisting of alkyl, alkoxy, aralkoxy, halo, haloalkyl, haloalkoxy,amino, alkylamino, and dialkylamino; R², R⁴ and R⁶ are eachindependently hydrogen or alkyl; each R³ is independently selected fromthe group consisting of alkyl, alkoxy, and halo; and each R^(5a) isindependently selected from the group consisting of alkyl, alkoxy,alkoxycarbonyl, halo, and aryl or two adjacent R^(5a) groups form anaryl, heterocyclyl or heteroaryl.
 16. The compound of claim 15 wherein mis 0 or 1, n is 1 and each R^(1a) is alkoxy.
 17. The compound of claim16 selected from the group consisting of the following:4-chloro-N-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]benzamide;3-methoxy-N-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]benzamide;4-methoxy-N-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]benzamide;4-tert-butyl-N-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]benzamide;N-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-terephthalamicacid methyl ester;2,4-dichloro-N-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]benzamide;benzo[1,3]dioxole-5-carboxylic acid[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]amide;benzo[1,3]dioxole-5-carboxylic acid{1-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;N-{1-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methyl-terephthalamicacid methyl ester;2-methoxy-N-{1-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl)-N-methylbenzamide;3-methoxy-N-{1-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzamide;4-methoxy-N-{1-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzamide;benzo[1,3]dioxole-5-carboxylic acid{1-[3-(4-methoxyphenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;4-tert-butyl-N-{1-[3-(4-methoxyphenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzamide;benzo[1,3]dioxole-5-carboxylic acid{1-[3-(4-methoxyphenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;4-tert-butyl-N-{1-[3-(4-methoxyphenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzamide;benzo[1,3]dioxole-5-carboxylic acid{1-[3-(4-methoxyphenyl)-6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;4-tert-butyl-N-{1-[3-(4-methoxyphenyl)-6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzamide;benzo[1,3]dioxole-5-carboxylic acid{1-[7-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;4-tert-butyl-N-{1-[7-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzamide;benzo[1,3]dioxole-5-carboxylic acid{1-[6-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;4-tert-butyl-N-{1-[6-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzamide;benzo[1,3]dioxole-5-carboxylic acid{1-[3-(4-methoxyphenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;4-tert-butyl-N-{1-[3-(4-methoxyphenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzamide;benzo[1,3]dioxole-5-carboxylic acid{1-[8-methoxy-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;4-tert-butyl-N-{1-[8-methoxy-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzamide;benzo[1,3]dioxole-5-carboxylic acid{1-[5-methoxy-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;4-tert-butyl-N-{1-[5-methoxy-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzamide;benzo[1,3]dioxole-5-carboxylic acid{1-[6-methoxy-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;4-tert-butyl-N-{1-[6-methoxy-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzamide;4-tert-butyl-N-{1-[3-(3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzamide;benzo[1,3]dioxole-5-carboxylic acid{1-[3-(3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;4-tert-butyl-N-{1-[3-(2-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzamide;benzo[1,3]dioxole-5-carboxylic acid{1-[3-(2-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;benzo[1,3]dioxole-5-carboxylic acid{1-[8-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;4-tert-butyl-N-{1-[8-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzamide;and4-tert-butyl-N-{1-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzamide.18. The compound of claim 15 wherein m is 0 or 1, n is 1, or 3 and eachR^(1a) is selected from alkyl.
 19. The compound of claim 18 selectedfrom the group consisting of the following:N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]benzamide;4-tert-butyl-N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]benzamide;benzo[1,3]dioxole-5-carboxylic acid[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]amide;2,4-dichloro-N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]benzamide;N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-terephthalamicacid methyl ester; benzo[1,3]dioxole-5-carboxylic acid{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methyl-terephthalamicacid methyl ester; benzo[1,3]dioxole-5-carboxylic acid[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]methylamide;4-tert-butyl-N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-N-methylbenzamide;4-tert-butyl-N-{1-[3-(3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzamide;benzo[1,3]dioxole-5-carboxylic acid{1-[3-(3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;4-tert-butyl-N-{1-[3-(4-tert-butyl-phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzamide;benzo[1,3]dioxole-5-carboxylic acid{1-[3-(4-tert-butyl-phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;4-tert-butyl-N-methyl-N-[1-(4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]-benzamide;benzo[1,3]dioxole-5-carboxylic acidmethyl-[1-(4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]amide;benzo[1,3]dioxole-5-carboxylic acid[1-(6-bromo-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]methylamide;andN-[1-(6-bromo-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]-4-tert-butyl-N-methylbenzamide.20. The compound of claim 15 wherein m is 0 or 1, n is 0 or 1 and eachR^(1a) is independently selected from dialkylamino, aralkoxy, halo,haloalkyl and haloalkoxy.
 21. The compound of claim 20 selected from thegroup consisting of the following: benzo[1,3]dioxole-5-carboxylic acid{1-[3-(4-dimethylamino-phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;4-tert-butyl-N-{1-[3-(4-dimethylamino-phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzamide;benzo[1,3]dioxole-5-carboxylic acid{1-[3-(4-benzyloxy-phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;N-{1-[3-(4-benzyloxy-phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-tert-butyl-N-methylbenzamide;N-{1-[3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-2-methoxy-N-methylbenzamide;N-{1-[3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-3-methoxy-N-methylbenzamide;N-{1-[3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-methoxy-N-methylbenzamide;benzo[1,3]dioxole-5-carboxylic acid{1-[3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;N-{1-[3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methyl-terephthalamicacid methyl ester;4-tert-butyl-N-{1-[3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzamide;4-tert-butyl-N-methyl-N-[1-(4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl]benzamide;benzo[1,3]dioxole-5-carboxylic acidmethyl-[1-(4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl]amide;benzo[1,3]dioxole-5-carboxylic acid{1-[3-(4-bromophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;N-{1-[3-(4-bromophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-tert-butyl-N-methylbenzamide;4-tert-butyl-N-methyl-N-{1-[4-oxo-3-(4-trifluoromethoxyphenyl)-3,4-dihydroquinazolin-2-yl]ethyl}benzamide;and benzo[1,3]dioxole-5-carboxylic acidmethyl-{1-[4-oxo-3-(4-trifluoromethoxyphenyl)-3,4-dihydroquinazolin-2-yl]ethyl}-amide;4-tert-butyl-N-{1-[3-(4-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzamide;benzo[1,3]dioxole-5-carboxylic acidmethyl-{1-[4-oxo-3-(4-trifluoromethylphenyl)-3,4-dihydroquinazolin-2-yl]ethyl}-amide;and4-tert-butyl-N-methyl-N-{1-[4-oxo-3-(4-trifluoromethylphenyl)-3,4-dihydroquinazolin-2-yl]ethyl}-benzamide.22. The compound of claim 1 wherein R¹ is hydrogen, optionallysubstituted alkyl, optionally substituted aryl, or optionallysubstituted aralkyl.
 23. (canceled)
 24. (canceled)
 25. The compound ofclaim 22 wherein R¹ is optionally substituted phenyl, and is selectedwith the proviso that it is not substituted at the 3- or 4-position with—C(OH)(CF₃)₂.
 26. The compound of claim 2 wherein any two R^(1a) or R³groups, which substitute adjacent carbons on the ring, together formalkylene, alkenylene, alkylenedioxy, thioalkylenoxy, oralkylenedithioxy.
 27. The compound of claim 2 wherein R^(1a) is not—C(OH)(CF₃)₂.
 28. The compound of claim 1 wherein R⁶ is hydrogen. 29.The compound of claim 1 wherein n is 0, 1 or
 2. 30. The compound ofclaim 1 wherein m is
 1. 31. The compound of claim 2 wherein each R^(1a)is independently halo, pseudohalo, optionally substituted alkyl,optionally substituted alkoxy, optionally substituted aryl, optionallysubstituted dialkylamino, optionally substituted aralkoxy, hydroxy,optionally substituted heteroaryl, optionally substituted heterocyclylor optionally substituted cycloalkyl.
 32. (canceled)
 33. The compound ofclaim 31 wherein each R^(1a) is independently chloro, fluoro, ethyl,methyl, methoxy, bromo, cyano, phenyl, tert-butyl, trifluoromethoxy,dimethylamino, trifluoromethyl, benzyloxy, hydroxy, 2-methylphenyl,3-methylphenyl, 4-methylphenyl, 2-chlorophenyl, 3-chlorophenyl,4-chlorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,ethoxy, isopropoxy, butoxy, isobutoxy, 2-(N-morpholino)ethoxy,2-methoxyethoxy, 4-cyanophenyl, 2-thienyl, 3-thienyl,3-methoxycarbonylphenyl, 4-methoxycarbonylphenyl, 3-carboxyphenyl,N-pyrrolidinyl, or N-morpholinyl.
 34. The compound of claim 1 wherein R²is hydrogen or optionally substituted alkyl, and R⁶ is hydrogen. 35.(canceled)
 36. The compound of claim 34 wherein R² is hydrogen, methylor ethyl.
 37. The compound of claim 1 wherein each R³ is independentlyoptionally substituted alkyl, halo, pseudohalo, optionally substitutedalkoxy, hydroxy, optionally substituted aralkoxy, optionally substitutedaryl, optionally substituted heteroaryl, optionally substitutedheterocyclyl, or optionally substituted cycloalkyl.
 38. (canceled) 39.The compound of claim 37 wherein each R³ is independently methyl,chloro, methoxy, hydroxy, bromo, ethoxy, isopropoxy, isobutoxy, butoxy,benzyloxy, ethoxycarbonylmethoxy, phenyl, 2-thienyl, 3-thienyl,2-methylphenyl, 3-methylphenyl, 4-methylpheny, 2-chlorophenyl,3-chlorophenyl, 4-chlorophenyl, 3-methoxyphenyl, 4-methoxyphenyl,4-carboxyphenyl, N-pyrrolidinyl, N-morpholinyl, 3-methoxycarbonylphenyl,4-methoxycarbonylphenyl, 3-carboxyphenyl, 4-cyanophenyl, or piperidinyl.40. The compound of claim 1 wherein one of R⁴ and R¹ is —SO₂—(optionally substituted aryl).
 41. The compound of claim 1 wherein oneof R⁴ and R⁵ is —SO₂— (optionally substituted phenyl).
 42. The compoundof claim 2 wherein the compound has formula (III):

or a pharmaceutically acceptable derivative thereof, wherein: t is aninteger from 0 to 5; R^(1a), R², R³, R⁴, R⁶, n and m are as definedabove; each R^(5a) is independently optionally substituted alkyl,optionally substituted alkoxy, optionally substituted heteroaryl,optionally substituted aryl, optionally substituted heterocyclyl, halo,pseudohalo; or any two R^(5a) substituents, which substitute adjacentatoms on the ring, together form a optionally substituted cycloalkyl,optionally substituted heterocyclyl, optionally substituted aryl, oroptionally substituted heteroaryl ring having 5 or 6 members in the ringand where the heteroatoms, if present, are selected from O, S andoptionally substituted N; where R^(5a), when substituted, is substitutedwith one or more, in one embodiment one to five, in another embodimentone, two or three, substituents each independently selected from Q¹, asdefined above.
 43. The compound of claim 42 wherein any two R^(5a)groups, which substitute adjacent carbons on the ring, together form—N═C(R²⁹)—C(R²⁹)═C(R²⁹)— or —C(R²⁹)═C(R²⁹)—C(R²⁹)═C(R²⁹)—, where eachR²⁹ is independently hydrogen, halo, pseudohalo, optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted aralkyl, or optionally substitutedheteroaralkyl; where R^(5a) and R²⁹, when substituted, are substitutedwith one or more, in one embodiment one to five, in another embodimentone, two or three, substituents each independently selected from Q¹, asdefined above.
 44. (canceled)
 45. The compound of claim 42 wherein eachR^(5a) is independently tert-butyl, methoxy, methyl, trifluoromethoxy,2-thienyl, fluoro, chloro, trifluoromethyl, phenyl, cyano, n-propyl,1,1-dimethylpropyl, isopropyl, butoxy or n-butyl; or any two R^(5a)groups, which substitute adjacent carbons on the ring, together form—N═C(H)—C(H)═CH— or —C(H)═C(H)—C(H)═C(H)—.
 46. The compound of claim 42wherein R⁴ is hydrogen, optionally substituted alkyl, optionallysubstituted aralkyl, or optionally substituted heteroaralkyl. 47.(canceled)
 48. The compound of claim 46 wherein R⁴ is hydrogen, methyl,2-methoxy-1-ethyl, propyl, isobutyl, butyl, pentyl, isopentyl, hexyl,benzyl, phenethyl or 2-thienylmethyl.
 49. The compound of claim 42wherein one R^(5a) group is 4-tert-butyl or 4-isopropyl.
 50. Thecompound of claim 2 wherein the compound has formula (IV):

or a pharmaceutically acceptable derivative thereof, wherein R^(1a), R²,R³, R⁴, R⁶, R^(5a), m and n are selected as above; u is an integer from0 to 4; and R^(5b) is tert-butyl or isopropyl.
 51. The compound of claim50 wherein R^(5b) is tert-butyl or isopropyl.
 52. (canceled)
 53. Thecompound of claim 1 wherein one of R⁴ and R⁵ is —C(O)— (optionallysubstituted aryl).
 54. The compound of claim 53 wherein one of R⁴ and R⁵is —C(O)— (optionally substituted phenyl).
 55. The compound of claim 2wherein the compound has formula (V):

or a pharmaceutically acceptable derivative thereof, wherein R^(1a), R²,R³, R⁴, R⁶, R^(5a), t, n and m are as defined above.
 56. The compound ofclaim 55 wherein each R^(1a) is independently halo, optionallysubstituted alkyl, or optionally substituted alkoxy, where thesubstituents, when present, are each independently selected from Q¹, asdefined above.
 57. (canceled)
 58. The compound of claim 56 wherein eachR^(1a) is independently methoxy, methyl, chloro or fluoro.
 59. Thecompound of claim 55 wherein R² is hydrogen or optionally substitutedalkyl, where the substituents, when present, are each independentlyselected from Q¹, as defined above.
 60. (canceled)
 61. The compound ofclaim 59 wherein R² is hydrogen or methyl.
 62. The compound of claim 55wherein each R³ is independently hydrogen or optionally substitutedalkoxy, where the substituents, when present, are each independentlyselected from Q¹, as defined above.
 63. (canceled)
 64. The compound ofclaim 62 wherein each R³ is independently hydrogen or methoxy.
 65. Thecompound of claim 55 wherein R⁴ is optionally substituted alkyl, wherethe substituents, when present, are each independently selected from Q¹,as defined above.
 66. (canceled)
 67. The compound of claim 65 wherein R⁴is methyl or butyl.
 68. The compound of claim 55 wherein R⁶ is hydrogen.69. The compound of claim 55 wherein each R^(5a) is independentlyoptionally substituted alkyl, where the substituents, when present, areeach independently selected from Q¹, as defined above.
 70. (canceled)71. The compound of claim 69 wherein R^(5a) is tert-butyl.
 72. Thecompound of claim 1 wherein one of R⁴ and R¹ is —C(O)— (optionallysubstituted alkyl), where the substituents, when present, are eachindependently selected from Q¹, as defined above.
 73. (canceled)
 74. Thecompound of claim 72 wherein one of R⁴ and R⁵ is —C(O)-octyl.
 75. Thecompound of claim 1 wherein one of R⁴ and R⁵ is —C(O)—N(R⁸)R⁹, where R⁸and R⁹ are each independently selected from hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkylalkyl, and optionallysubstituted heterocyclylalkyl; or R⁸ and R⁹ together form alkylene,alkenylene, alkyleneoxyalkylene or alkyleneazaalkylene; where R⁸ and R⁹are each independently unsubstituted or substituted with one or more, inone embodiment one to five, in another embodiment one, two or three,substituents each independently selected from Q¹, as defined above. 76.The compound of claim 75 wherein R⁸ and R⁹ are each independentlyselected from hydrogen, optionally substituted cycloalkyl, andoptionally substituted aryl.
 77. (canceled)
 78. The compound of claim 76wherein R⁸ is hydrogen and R⁹ is cyclohexyl, 4-nitrophenyl,2-methoxyphenyl, 3-cyanophenyl, 3,4-dichlorophenyl,2,6-diisopropylphenyl, 2-methylphenyl, 2-trifluoromethylphenyl,2-fluorophenyl, 3-fluorophenyl, 3-methylphenyl, 3-chlorophenyl,2,6-dimethylphenyl or 3-trifluoromethylphenyl.
 79. (canceled)
 80. Thecompound of claim 1 wherein R⁴ and R⁵ together form—CH₂—C(H)(Me)—N(R³⁰)—CH₂—CH₂—, where R³⁰ is optionally substitutedheteroarylcarbonyl, optionally substituted alkylcarbonyl, optionallysubstituted arylcarbonyl, optionally substituted arylsulfonyl,optionally substituted alkylaminocarbonyl, or optionally substitutedarylaminocarbonyl.
 81. The compound of claim 80 wherein R³⁰ is2-thienylcarbonyl, butyryl, 4-fluorobenzoyl, benzyloxyacetyl,diphenylacetyl, 4-nitrobenzoyl, 2,5-dichlorobenzenesulfonyl,tert-butylaminocarbonyl, phenylaminocarbonyl,2,3-dichlorophenylaminocarbonyl, 4-tert-butylphenylsulfonyl or3,4-methylenedioxybenzoyl.
 82. (canceled)
 83. The compound of claim 1wherein Q² is nitro, fluoro, benzyloxy or chloro; or any two Q² groups,which substitute adjacent carbons, together form methylenedioxy.
 84. Amethod of treating, preventing, or ameliorating the symptoms of adisease or disorder that is modulated or otherwise affected by nuclearreceptor activity or in which nuclear receptor activity is implicated,comprising administering to a subject in need thereof an effectiveamount of a compound of 3 claim
 1. 85. The method of claim 84, whereinthe disease or disorder is selected from hypercholesterolemia,hyperlipoproteinemia, hypertriglyceridemia, lipodystrophy,hyperglycemia, diabetes mellitus, dyslipidemia, atherosclerosis,gallstone disease, acne vulgaris, acneiform skin conditions, diabetes,Parkinson's disease, cancer, Alzheimer's disease, inflammation,immunological disorders, lipid disorders, obesity, conditionscharacterized by a perturbed epidermal barrier function, hyperlipidemia,cholestasis, peripheral occlusive disease, ischemic stroke, conditionsof disturbed differentiation or excess proliferation of the epidermis ormucous membrane, and cardiovascular disorders.
 86. A method of reducingcholesterol levels in a subject in need thereof, comprisingadministering an effective amount of a compound of claim
 1. 87. A methodof treating, preventing, or ameliorating one or more symptoms of adisease or disorder which is affected by cholesterol, triglyceride, orbile acid levels, comprising administering to a subject in need thereofan effective amount of a compound of claim
 1. 88. A method of modulatingnuclear receptor activity, comprising contacting the nuclear receptorwith a compound claim
 1. 89. The method of claim 88, wherein the nuclearreceptor is an orphan nuclear receptor.
 90. The method of claim 88,wherein the nuclear receptor is farnesoid X receptor (FXR).
 91. Themethod of claim 88, wherein the compound is a nuclear receptor agonist.92. The method of claim 88, wherein the compound is a nuclear receptorantagonist.
 93. A method of modulating cholesterol metabolism,comprising administering an effective amount of a compound of claim 1.94. A method of treating, preventing or ameliorating one or moresymptoms of hypocholesterolemia in a subject in need thereof, comprisingadministering an effective amount of a compound of claim
 1. 95. A methodof increasing cholesterol efflux from cells of a subject, comprisingadministering an effective amount of a compound of claim
 1. 96. A methodof increasing the expression of ATP-Binding Cassette (ABC1) in the cellsof a subject, comprising administering an effective amount of a compoundof claim
 1. 97. An in vitro method for altering nuclear receptoractivity, comprising contacting the nuclear receptor with a compound ofclaim
 1. 98. The method of claim 84, wherein a second active agentselected from antihyperlipidemic agents, plasma HDL-raising agents,antihypercholesterolemic agents, cholesterol biosynthesis inhibitors(such as HMG CoA reductase inhibitors, such as lovastatin, simvastatin,pravastatin, fluvastatin, atorvastatin and rivastatin), acyl-coenzymeA:cholesterol acytransferase (ACAT) inhibitors, probucol, raloxifene,nicotinic acid, niacinamide, cholesterol absorption inhibitors, bileacid sequestrants (such as anion exchange resins, or quaternary amines(e.g., cholestyramine or colestipol)), low density lipoprotein receptorinducers, clofibrate, fenofibrate, benzofibrate, cipofibrate,gemfibrizol, vitamin B₆, vitamin B₁₂, anti-oxidant vitamins, 8-blockers,anti-diabetes agents, angiotensin II antagonists, angiotensin convertingenzyme inhibitors, platelet aggregation inhibitors, fibrinogen receptorantagonists, aspirin and fibric acid derivatives; is administeredsimultaneously with, prior to, or after administration of the compound.99. A pharmaceutical composition, comprising, in a pharmaceuticallyacceptable carrier, a compound of formula (I):

wherein: m is an integer from 0 to 4; R¹ is hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkylalkyl, optionallysubstituted heterocyclylalkyl, —OR⁷ or —N(R⁸)R⁹, with the proviso thatR¹ is not 3- or 4-(1,1,1,3,3,3-hexafluoro-2-hydroxy-2-propyl)phenyl; R²,R⁴, R⁵ and R⁶ are selected from (a) and (b) as follows: (a) R² and R⁶are selected from (i) and (ii) as follows: (i) R² and R⁶ are eachindependently hydrogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted cycloalkyl, optionally substituted heterocyclyl, optionallysubstituted aralkyl, optionally substituted heteroaralkyl, optionallysubstituted cycloalkylalkyl, or optionally substitutedheterocyclylalkyl; or (ii) R² and R⁶ together form optionallysubstituted alkylene or optionally substituted alkenylene; and R⁴ and R⁵are selected from (i) and (ii) as follows: (i) R⁴ and R⁵ are eachindependently selected from hydrogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted cycloalkyl, optionally substituted heterocyclyl,optionally substituted aralkyl, optionally substituted heteroaralkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocyclylalkyl, —N(R⁸)R⁹), —OR⁷, —S(O)_(j)R¹¹ where j is 1 or 2,—B(R²²)₂, —P(R²²)₂, —P(O)(R²²)₂ and —C(E)R²³, where E is selected fromO, S and NR⁷; or (ii) R⁴ and R⁵ together form optionally substitutedalkylene, optionally substituted alkenylene, optionally substitutedalkyleneoxyalkylene or optionally substituted alkyleneazaalkylene; or(b) R² and R⁵, or R² and R⁴, or R⁶ and R⁵, or R⁶ and R⁴, together form a4, 5, 6 or 7 membered optionally substituted heterocyclyl group, or a 5or 6 membered optionally substituted heteroaryl group; and the remainderof R², R², R⁵ and R⁶ are each independently selected as in (i) above;each R³ is independently selected from the group consisting of halo,pseudohalo, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, optionally substituted aralkyl,optionally substituted heteroaralkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocyclylalkyl, —N(R¹²)R¹³,—OR¹⁴, —C(E)R¹⁵ where E is O, S or NR⁷, and —S(O)_(y)R¹⁶ where y is 0, 1or 2; or any two R³ groups, which substitute adjacent carbons on thering, together form optionally substituted alkylene, optionallysubstituted alkenylene, optionally substituted alkylenedioxy, optionallysubstituted thioalkylenoxy, or optionally substituted alkylenedithioxy;each R⁷ is independently selected from the group consisting of hydrogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkylalkyl, and optionallysubstituted heterocyclylalkyl; R⁸ and R⁹ are each independently selectedfrom hydrogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, optionally substituted aralkyl,optionally substituted heteroaralkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocyclylalkyl, —S(O)_(j)R¹⁰where j is 1 or 2, and —C(M)R¹¹, where M is selected from O and S; or R⁸and R⁹ together form alkylene, alkenylene, alkyleneoxyalkylene oralkyleneazaalkylene; each R¹⁰ is independently selected from the groupconsisting of optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, optionally substituted aralkyl,optionally substituted heteroaralkyl, optionally substitutedcycloalkylalkyl, and optionally substituted heterocyclylalkyl; each R¹¹is independently selected from the group consisting of optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkylalkyl, optionallysubstituted heterocyclylalkyl, —OR¹⁰ and —N(R⁷)₂; R¹² and R¹³ are eachindependently selected from hydrogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted cycloalkyl, optionally substituted heterocyclyl,optionally substituted aralkyl, optionally substituted heteroaralkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocyclylalkyl, —C(M)R¹⁷ where M is O or S, and —S(O)_(j)R¹⁸ where jis 1 or 2; or R¹² and R¹³ together form optionally substituted alkylene,optionally substituted alkenylene, optionally substitutedalkyleneoxyalkylene or optionally substituted alkyleneazaalkylene; R¹⁴is hydrogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, optionally substituted aralkyl,optionally substituted heteroaralkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocyclylalkyl or —C(M)R¹⁷where M is O or S; R¹⁵ is hydrogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted cycloalkyl, optionally substituted heterocyclyl,optionally substituted aralkyl, optionally substituted heteroaralkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocyclylalkyl, —OH, —OR¹⁴ or —N(R¹²)R¹³; R¹⁶ is hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkylalkyl, optionallysubstituted heterocyclylalkyl, —OH, —OR¹⁹ or —N(R²⁰)R²¹; R¹⁷ ishydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted cycloalkyl, optionallysubstituted heterocyclyl, optionally substituted aralkyl, optionallysubstituted heteroaralkyl, optionally substituted cycloalkylalkyl,optionally substituted heterocyclylalkyl, —OR¹⁹ or —N(R²⁰)R²¹; R¹⁸ isoptionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkylalkyl, optionallysubstituted heterocyclylalkyl, —OR¹⁹ or —N(R²⁰)R²¹; R¹⁹ is alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl,heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; R²⁰ andR²¹ are each independently selected from hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,aryl, heteroaryl, aralkyl and heteroaralkyl, or R²⁰ and R²¹ togetherform alkylene, alkenylene, alkyleneoxyalkylene or alkyleneazaalkylene;each R²² is independently selected from the group consisting ofoptionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkylalkyl, optionallysubstituted heterocyclylalkyl, —OR⁷ and —N(R⁷)₂; R²³ is hydrogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkylalkyl, optionallysubstituted heterocyclylalkyl, —OR¹⁰, —N(R⁷)₂, or —N(R⁷)N(R⁷)₂; whereineach of the above R¹-R²³ groups, when substituted, are substituted withone or more substituents each independently selected from Q¹, where Q¹is halo, pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl,mercapto, carboxy, carboxyalkyl, alkyl, haloalkyl, polyhaloalkyl,aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds,alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl,aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl,alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene,alkylcarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyl, arylcarbonyl,heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl,aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl,aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl,diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy,heteroaryloxy, heteroaralkoxy, heterocyclyloxy, heterocyclylalkoxy,cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy,alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy,aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl,alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl,alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino,arylamino, diarylamino, alkylarylamino, alkylcarbonylamino,alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino,arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺(R²⁴)₃, —P(R²⁵)₂, —P(O)(R²⁵)₂, —OP(O)(R²⁵)₂,—N(R²⁴)C(O)R²⁶, dialkylphosphonyl, alkylarylphosphonyl,diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio,perfluoroalkylthio, carboxyalkylthio, thiocyano, isothiocyano,alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy,hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy,alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy,diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl,alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl,alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl,arylaminosulfonyl, diarylaminosulfonyl or alkylarylaminosulfonyl; or twoQ¹ groups, which substitute atoms in a 1,2 or 1,3 arrangement, togetherform alkylenedioxy (i.e., —O—(CH₂)_(y)—O—), thioalkylenoxy (i.e.,—S—(CH₂)_(y)—O—) or alkylenedithioxy (i.e., —S—(CH₂)_(y)—S—) where y is1 or 2; or two Q¹ groups, which substitute the same atom, together formalkylene; each R²⁴ is independently selected from the group consistingof hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl and heterocyclylalkyl; each R²⁵ is independently selectedfrom the group consisting of hydroxy, alkoxy, aralkoxy, alkyl,heteroaryl, heterocyclyl, aryl and —N(R²⁷)R²⁸, R²⁶ is alkoxy, aralkoxy,alkyl, heteroaryl, heterocyclyl, aryl or —N(R²⁷)R²⁸; R²⁷ and R²⁸ areeach independently hydrogen, alkyl, aralkyl, aryl, heteroaryl,heteroaralkyl or heterocyclyl, or R²⁷ and R²⁸ together form alkylene,azaalkylene, oxaalkylene or thiaalkylene; and each Q¹ is optionallysubstituted by one or more substituents selected from Q²; where each Q²is independently halo, pseudohalo, hydroxy, oxo, thia, nitrile, nitro,formyl, mercapto, carboxy, carboxyalkyl, alkyl, haloalkyl,polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl,aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl,dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene,arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl,aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl,arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl,arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy,heterocyclyloxy, heterocyclylalkoxy, cycloalkoxy, perfluoroalkoxy,alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy,aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy,aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy,dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy,diarylaminocarbonyloxy, guanidino, isothioureido, amidino, alkylamidino,arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl,arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl,alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino,arylamino, diarylamino, alkylarylamino, alkylcarbonylamino,alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino,arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺(R²⁴)₃, —P(R²⁵)₂, —P(O)(R²⁵)₂, —OP(O)(R²⁵)₂,—N(R²¹)C(O)R²⁶, dialkylphosphonyl, alkylarylphosphonyl,diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio,perfluoroalkylthio, carboxyalkylthio, thiocyano, isothiocyano,alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy,hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy,alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy,diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl,alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl,alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl,arylaminosulfonyl, diarylaminosulfonyl or alkylarylaminosulfonyl; or twoQ² groups, which substitute atoms in a 1,2 or 1,3 arrangement, togetherform alkylenedioxy (i.e., —O—(CH₂)_(y)—O—), thioalkylenoxy (i.e.,—S—(CH₂)_(y)—O—) or alkylenedithioxy (i.e., —S—(CH₂)_(y)—S—) where y is1 or 2; or two Q² groups, which substitute the same atom, together formalkylene, where R²⁴, R²⁵, R²⁶, R²⁷ and R²⁸ are as defined above; as astereoisomer, racemate or mixture thereof; or as a pharmaceuticallyacceptable derivative thereof
 100. A pharmaceutical composition,comprising, in a pharmaceutically acceptable carrier: (i) a compound offormula (I):

wherein: m is an integer from 0 to 4; R¹ is hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkylalkyl, optionallysubstituted heterocyclylalkyl, —OR⁷ or —N(R⁸)R⁹, with the proviso thatR¹ is not 3- or 4-(1,1,1,3,3,3-hexafluoro-2-hydroxy-2-propyl)phenyl; R²,R⁴, R⁵ and R⁶ are selected from (a) and (b) as follows: (a) R² and R⁶are selected from (i) and (ii) as follows: (i) R² and R⁶ are eachindependently hydrogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted cycloalkyl, optionally substituted heterocyclyl, optionallysubstituted aralkyl, optionally substituted heteroaralkyl, optionallysubstituted cycloalkylalkyl, or optionally substitutedheterocyclylalkyl; or (ii) R² and R⁶ together form optionallysubstituted alkylene or optionally substituted alkenylene; and R⁴ and R⁵are selected from (i) and (ii) as follows: (i) R⁴ and R⁵ are eachindependently selected from hydrogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted cycloalkyl, optionally substituted heterocyclyl,optionally substituted aralkyl, optionally substituted heteroaralkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocyclylalkyl, —N(R⁸)R⁹), —OR⁷, —S(O)_(j)R¹¹ where j is 1 or 2,—B(R²²)₂, —P(R²²)₂, —P(O)(R²²)₂ and —C(E)R²³, where E is selected fromO, S and NR⁷; or (ii) R⁴ and R⁵ together form optionally substitutedalkylene, optionally substituted alkenylene, optionally substitutedalkyleneoxyalkylene or optionally substituted alkyleneazaalkylene; or(b) R² and R⁵, or R² and R⁴, or R⁶ and R⁵, or R⁶ and R⁴, together form a4, 5, 6 or 7 membered optionally substituted heterocyclyl group, or a 5or 6 membered optionally substituted heteroaryl group; and the remainderof R², R⁴, R⁵ and R⁶ are each independently selected as in (i) above;each R³ is independently selected from the group consisting of halo,pseudohalo, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, optionally substituted aralkyl,optionally substituted heteroaralkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocyclylalkyl, —N(R¹²)R¹³,—OR¹⁴, —C(E)R¹⁵ where E is O, S or NR⁷, and —S(O)_(y)R¹⁶ where y is 0, 1or 2; or any two R³ groups, which substitute adjacent carbons on thering, together form optionally substituted alkylene, optionallysubstituted alkenylene, optionally substituted alkylenedioxy, optionallysubstituted thioalkylenoxy, or optionally substituted alkylenedithioxy;each R⁷ is independently selected from the group consisting of hydrogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkylalkyl, and optionallysubstituted heterocyclylalkyl; R⁸ and R⁹ are each independently selectedfrom hydrogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, optionally substituted aralkyl,optionally substituted heteroaralkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocyclylalkyl, —S(O)_(j)R¹⁰where j is 1 or 2, and —C(M)R¹¹, where M is selected from O and S; or R⁸and R⁹ together form alkylene, alkenylene, alkyleneoxyalkylene oralkyleneazaalkylene; each R¹⁰ is independently selected from the groupconsisting of optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, optionally substituted aralkyl,optionally substituted heteroaralkyl, optionally substitutedcycloalkylalkyl, and optionally substituted heterocyclylalkyl; each R¹¹is independently selected from the group consisting of optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkylalkyl, optionallysubstituted heterocyclylalkyl, —OR¹⁰ and —N(R⁷)₂; R¹² and R¹³ are eachindependently selected from hydrogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted cycloalkyl, optionally substituted heterocyclyl,optionally substituted aralkyl, optionally substituted heteroaralkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocyclylalkyl, —C(M)R¹⁷ where M is O or S, and —S(O)_(j)R¹⁸ where jis 1 or 2; or R¹² and R¹³ together form optionally substituted alkylene,optionally substituted alkenylene, optionally substitutedalkyleneoxyalkylene or optionally substituted alkyleneazaalkylene; R¹⁴is hydrogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, optionally substituted aralkyl,optionally substituted heteroaralkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocyclylalkyl or —C(M)R¹⁷where M is O or S; R¹⁵ is hydrogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted cycloalkyl, optionally substituted heterocyclyl,optionally substituted aralkyl, optionally substituted heteroaralkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocyclylalkyl, —OH, —OR¹⁴ or —N(R¹²)R¹³. R¹⁶ is hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkylalkyl, optionallysubstituted heterocyclylalkyl, —OH, —OR¹⁹ or —N(R²⁰)R²¹; R¹⁷ ishydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted cycloalkyl, optionallysubstituted heterocyclyl, optionally substituted aralkyl, optionallysubstituted heteroaralkyl, optionally substituted cycloalkylalkyl,optionally substituted heterocyclylalkyl, —OR¹⁹ or —N(R²⁰)R²¹; R¹⁸ isoptionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkylalkyl, optionallysubstituted heterocyclylalkyl, —OR¹⁹ or —N(R²⁰)R²¹; R¹⁹ is alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl,heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; R²⁰ andR²¹ are each independently selected from hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,aryl, heteroaryl, aralkyl and heteroaralkyl, or R²⁰ and R²¹ togetherform alkylene, alkenylene, alkyleneoxyalkylene or alkyleneazaalkylene;each R²² is independently selected from the group consisting ofoptionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkylalkyl, optionallysubstituted heterocyclylalkyl, —OR⁷ and —N(R⁷)₂; R²³ is hydrogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkylalkyl, optionallysubstituted heterocyclylalkyl, —OR¹⁰, —N(R⁷)₂, or —N(R⁷)N(R⁷)₂; whereineach of the above R¹-R²³ groups, when substituted, are substituted withone or more substituents each independently selected from Q¹, where Q¹is halo, pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl,mercapto, carboxy, carboxyalkyl, alkyl, haloalkyl, polyhaloalkyl,aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds,alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl,aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl,alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene,alkylcarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyl, arylcarbonyl,heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl,aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl,aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl,diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy,heteroaryloxy, heteroaralkoxy, heterocyclyloxy, heterocyclylalkoxy,cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy,alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy,aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl,alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl,alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino,arylamino, diarylamino, alkylarylamino, alkylcarbonylamino,alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino,arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺(R²⁴)₃, —P(R²⁵)₂, —P(O)(R²⁵)₂, —OP(O)(R²⁵)₂,—N(R²⁴)C(O)R²⁶, dialkylphosphonyl, alkylarylphosphonyl,diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio,perfluoroalkylthio, carboxyalkylthio, thiocyano, isothiocyano,alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy,hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy,alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy,diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl,alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl,alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl,arylaminosulfonyl, diarylaminosulfonyl or alkylarylaminosulfonyl; or twoQ¹ groups, which substitute atoms in a 1,2 or 1,3 arrangement, togetherform alkylenedioxy (i.e., —O—(CH₂)_(y)—O—), thioalkylenoxy (i.e.,—S—(CH₂)_(y)—O—) or alkylenedithioxy (i.e., —S—(CH₂)_(y)—S—) where y is1 or 2; or two Q¹ groups, which substitute the same atom, together formalkylene; each R²⁴ is independently selected from the group consistingof hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl and heterocyclylalkyl; each R²⁵ is independently selectedfrom the group consisting of hydroxy, alkoxy, aralkoxy, alkyl,heteroaryl, heterocyclyl, aryl and —N(R²⁷)R²⁸, R²⁶ is alkoxy, aralkoxy,alkyl, heteroaryl, heterocyclyl, aryl or —N(R²⁷)R²⁸; R²⁷ and R²⁸ areeach independently hydrogen, alkyl, aralkyl, aryl, heteroaryl,heteroaralkyl or heterocyclyl, or R²⁷ and R²⁸ together form alkylene,azaalkylene, oxaalkylene or thiaalkylene; and each Q¹ is optionallysubstituted by one or more substituents selected from Q²; where each Q²is independently halo, pseudohalo, hydroxy, oxo, thia, nitrile, nitro,formyl, mercapto, carboxy, carboxyalkyl, alkyl, haloalkyl,polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl,aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl,dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene,arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl,aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl,arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl,arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy,heterocyclyloxy, heterocyclylalkoxy, cycloalkoxy, perfluoroalkoxy,alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy,aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy,aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy,dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy,diarylaminocarbonyloxy, guanidino, isothioureido, amidino, alkylamidino,arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl,arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl,alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino,arylamino, diarylamino, alkylarylamino, alkylcarbonylamino,alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino,arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺(R²⁴)₃, —P(R²⁵)₂, —P(O)(R²⁵)₂, —OP(O)(R²⁵)₂,—N(R²⁴)C(O)R²⁶, dialkylphosphonyl, alkylarylphosphonyl,diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio,perfluoroalkylthio, carboxyalkylthio, thiocyano, isothiocyano,alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy,hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy,alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy,diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl,alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl,alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl,arylaminosulfonyl, diarylaminosulfonyl or alkylarylaminosulfonyl; or twoQ² groups, which substitute atoms in a 1,2 or 1,3 arrangement, togetherform alkylenedioxy (i.e., —O—(CH₂)_(y)—O—), thioalkylenoxy (i.e.,—S—(CH₂)_(y)—O—) or alkylenedithioxy (i.e., —S—(CH₂)_(y)—S—) where y is1 or 2; or two Q² groups, which substitute the same atom, together formalkylene, where R²⁴, R²⁵, R²⁶, R²⁷ and R²⁸ are as defined above; as astereoisomer, racemate or mixture thereof; or as a pharmaceuticallyacceptable derivative thereof; and (ii) one or more of a second activeagent selected from antihyperlipidemic agents, plasma HDL-raisingagents, antihypercholesterolemic agents, cholesterol biosynthesisinhibitors (such as HMG CoA reductase inhibitors, such as lovastatin,simvastatin, pravastatin, fluvastatin, atorvastatin and rivastatin),acyl-coenzyme A:cholesterol acytransferase (ACAT) inhibitors, probucol,raloxifene, nicotinic acid, niacinamide, cholesterol absorptioninhibitors, bile acid sequestrants (such as anion exchange resins, orquaternary amines (e.g., cholestyramine or colestipol)), low densitylipoprotein receptor inducers, clofibrate, fenofibrate, benzofibrate,cipofibrate, gemfibrizol, vitamin B₆, vitamin B₁₂, anti-oxidantvitamins, β-blockers, LXR □ or

agonists or antagonists, anti-diabetes agents, angiotensin IIantagonists, angiotensin converting enzyme inhibitors, plateletaggregation inhibitors, fibrinogen receptor antagonists, aspirin andfibric acid derivatives.
 101. A compound of claim 1 selected from thegroup consisting of the following: 2-naphthalen-1-yl-ethanesulfonic acid{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methyl-C-phenyl-methanesulfonamide;2-phenyl-ethenesulfonic acid{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;thiophene-2-sulfonic acid{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;C-(7,7-dimethyl-2-oxo-bicyclo[2.2.1]hept-1-yl)-N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methyl-methanesulfonamide;3,5-dimethyl-isoxazole-4-sulfonic acid{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methyl-methanesulfonamide;octane-1-sulfonic acid[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]methylamide;2-naphthalen-1-yl-ethanesulfonic acid[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]methylamide;2-phenyl-ethenesulfonic acid[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]methylamide;thiophene-2-sulfonic acid[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]methylamide;C-(7,7-dimethyl-2-oxo-bicyclo[2.2.1]hept-1-yl)-N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-N-methyl-methanesulfonamide;N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-N-methylmethanesulfonamide;butane-1-sulfonic acid[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]methylamide;3-chloropropane-1-sulfonic acid[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]methylamide;[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]-carbamicacid benzyl ester; nonanoic acid{1-[3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;nonanoic acid[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]amide;nonanoic acid{1-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;nonanoic acid{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide;4-tert-butyl-N-methyl-N-[1-(3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl]benzenesulfonamide;4-isopropyl-N-methyl-N-[1-(3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl]benzenesulfonamide;biphenyl-4-sulfonic acidmethyl-[1-(3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl]amide;4-methoxy-N-methyl-N-[1-(3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl]benzenesulfonamide;4-chloro-N-methyl-N-[1-(3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl]benzenesulfonamide;4-tert-butyl-N-methyl-N-[1-(3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl]benzamide;3-(4-methoxyphenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one;3-(3,5-dimethylphenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one;2-(1-methylaminoethyl)-3-phenyl-3H-quinazolin-4-one;3-(4-bromophenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one;3-(4-methoxyphenyl)-7-methyl-2-(1-methylaminoethyl)-3H-quinazolin-4-one;8-methoxy-3-(4-methoxyphenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one;5-methoxy-3-(4-methoxyphenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one;6-methoxy-3-(4-methoxyphenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one;3-(4-dimethylamino-phenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one;3-(4-fluorophenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one;4-tert-butyl-N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-dimethylbenzenesulfonamide,4-tert-butyl-N-{1-[6-methoxy-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide:4-tert-butyl-N-{1-[3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-ter-t-butyl-N-{1-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-tert-butyl-N-methyl-N-[1-(4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]benzenesulfonamide;4-tert-butyl-N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-tert-butyl-N-{1-[3-(4-methoxyphenyl)-6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide;4-tert-butyl-N-{1-[6-chloro-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide:N-{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-isopropyl-N-methylbenzenesulfonamide;and biphenyl-4-sulfonic acid{1-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}methylamide.102. (canceled)
 103. The compound of claim 50 having one or morefeatures selected from the group consisting of the following: a) R^(1a)is selected from the group consisting of alkyl, hydroxy, alkoxyalkoxyalkoxy and aralkoxy; b) R⁴ is hydrogen or alkyl; c) R³ isindependently selected from the group consisting of hydrogen, alkyl,alkoxy and halo; and d) R^(5a) is independently selected from the groupconsisting of alkyl, alkoxy, halo and alkylcarbonyl.
 104. The compoundof claim 103 having one or more features selected from the groupconsisting of the following: a) R^(1a) is alkoxy; b) R⁴ is alkyl; c) R³is selected from the group consisting of hydrogen, halo, alkoxy andalkyl; and d) R^(5a) is selected from the group consisting of tert-butyland isopropyl.